Adjustment of interaural time difference in head related transfer functions based on listeners' anthropometry and its effect on sound localization

NASA Astrophysics Data System (ADS)

Suzuki, Yôiti; Watanabe, Kanji; Iwaya, Yukio; Gyoba, Jiro; Takane, Shouichi

2005-04-01

Because the transfer functions governing subjective sound localization (HRTFs) show strong individuality, sound localization systems based on synthesis of HRTFs require suitable HRTFs for individual listeners. However, it is impractical to obtain HRTFs for all listeners based on measurements. Improving sound localization by adjusting non-individualized HRTFs to a specific listener based on that listener's anthropometry might be a practical method. This study first developed a new method to estimate interaural time differences (ITDs) using HRTFs. Then correlations between ITDs and anthropometric parameters were analyzed using the canonical correlation method. Results indicated that parameters relating to head size, and shoulder and ear positions are significant. Consequently, it was attempted to express ITDs based on listener's anthropometric data. In this process, the change of ITDs as a function of azimuth angle was parameterized as a sum of sine functions. Then the parameters were analyzed using multiple regression analysis, in which the anthropometric parameters were used as explanatory variables. The predicted or individualized ITDs were installed in the nonindividualized HRTFs to evaluate sound localization performance. Results showed that individualization of ITDs improved horizontal sound localization.

Combination of individual tree detection and area-based approach in imputation of forest variables using airborne laser data

NASA Astrophysics Data System (ADS)

Vastaranta, Mikko; Kankare, Ville; Holopainen, Markus; Yu, Xiaowei; Hyyppä, Juha; Hyyppä, Hannu

2012-01-01

The two main approaches to deriving forest variables from laser-scanning data are the statistical area-based approach (ABA) and individual tree detection (ITD). With ITD it is feasible to acquire single tree information, as in field measurements. Here, ITD was used for measuring training data for the ABA. In addition to automatic ITD (ITD auto), we tested a combination of ITD auto and visual interpretation (ITD visual). ITD visual had two stages: in the first, ITD auto was carried out and in the second, the results of the ITD auto were visually corrected by interpreting three-dimensional laser point clouds. The field data comprised 509 circular plots ( r = 10 m) that were divided equally for testing and training. ITD-derived forest variables were used for training the ABA and the accuracies of the k-most similar neighbor ( k-MSN) imputations were evaluated and compared with the ABA trained with traditional measurements. The root-mean-squared error (RMSE) in the mean volume was 24.8%, 25.9%, and 27.2% with the ABA trained with field measurements, ITD auto, and ITD visual, respectively. When ITD methods were applied in acquiring training data, the mean volume, basal area, and basal area-weighted mean diameter were underestimated in the ABA by 2.7-9.2%. This project constituted a pilot study for using ITD measurements as training data for the ABA. Further studies are needed to reduce the bias and to determine the accuracy obtained in imputation of species-specific variables. The method could be applied in areas with sparse road networks or when the costs of fieldwork must be minimized.

MIZMAS: Modeling the Evolution of Ice Thickness and Floe Size Distributions in the Marginal Ice Zone of the Chukchi and Beaufort Seas

DTIC Science & Technology

2015-09-30

ITD theory of Thorndike et al. (1975) in order to explicitly simulate the evolution of FSD and ITD jointly. The FSD theory includes a FSD function and...et al., 2015). 4 RESULTS Modeling: A FSD theory is developed and coupled to the ITD theory of Thorndike et al. (1975) in order to... Thorndike , A.S., D.A. Rothrock, G.A. Maykut, and R. Colony (1975), The thickness distribution of sea ice. J. Geophys. Res., 80, 4501–4513. Zhang

High Speed Research Program Structural Acoustics Multi-Year Summary Report

NASA Technical Reports Server (NTRS)

Beier, Theodor H.; Bhat, Waman V.; Rizzi, Stephen A.; Silcox, Richard J.; Simpson, Myles A.

2005-01-01

This report summarizes the work conducted by the Structural Acoustics Integrated Technology Development (ITD) Team under NASA's High Speed Research (HSR) Phase II program from 1993 to 1999. It is intended to serve as a reference for future researchers by documenting the results of the interior noise and sonic fatigue technology development activities conducted during this period. For interior noise, these activities included excitation modeling, structural acoustic response modeling, development of passive treatments and active controls, and prediction of interior noise. For sonic fatigue, these activities included loads prediction, materials characterization, sonic fatigue code development, development of response reduction techniques, and generation of sonic fatigue design requirements. Also included are lessons learned and recommendations for future work.

The role of HOXB2 and HOXB3 in acute myeloid leukemia.

PubMed

Lindblad, Oscar; Chougule, Rohit A; Moharram, Sausan A; Kabir, Nuzhat N; Sun, Jianmin; Kazi, Julhash U; Rönnstrand, Lars

2015-11-27

Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of AML patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML. We show that HOXB2 and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERK, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as tumor suppressors in FLT3-ITD driven AML. Copyright © 2015 Elsevier Inc. All rights reserved.

The role of HOXB2 and HOXB3 in acute myeloid leukemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindblad, Oscar; Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund; Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund

2015-11-27

Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of AML patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML. We show that HOXB2more » and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERK, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as tumor suppressors in FLT3-ITD driven AML.« less

Information Technology and Disabilities, 1996.

ERIC Educational Resources Information Center

McNulty, Tom, Ed.

1996-01-01

This document consists of all issues/pages of the electronic journal "Information Technology and Disabilities" published during 1996, i.e., a total of 13 ITD articles: (1) "New CSUF (California State University at Fullerton) Braille Transcription Center Promotes Access to Postsecondary Instructional Materials for the California State University…

Envelope contributions to the representation of interaural time difference in the forebrain of barn owls.

PubMed

Tellers, Philipp; Lehmann, Jessica; Führ, Hartmut; Wagner, Hermann

2017-09-01

Birds and mammals use the interaural time difference (ITD) for azimuthal sound localization. While barn owls can use the ITD of the stimulus carrier frequency over nearly their entire hearing range, mammals have to utilize the ITD of the stimulus envelope to extend the upper frequency limit of ITD-based sound localization. ITD is computed and processed in a dedicated neural circuit that consists of two pathways. In the barn owl, ITD representation is more complex in the forebrain than in the midbrain pathway because of the combination of two inputs that represent different ITDs. We speculated that one of the two inputs includes an envelope contribution. To estimate the envelope contribution, we recorded ITD response functions for correlated and anticorrelated noise stimuli in the barn owl's auditory arcopallium. Our findings indicate that barn owls, like mammals, represent both carrier and envelope ITDs of overlapping frequency ranges, supporting the hypothesis that carrier and envelope ITD-based localization are complementary beyond a mere extension of the upper frequency limit. NEW & NOTEWORTHY The results presented in this study show for the first time that the barn owl is able to extract and represent the interaural time difference (ITD) information conveyed by the envelope of a broadband acoustic signal. Like mammals, the barn owl extracts the ITD of the envelope and the carrier of a signal from the same frequency range. These results are of general interest, since they reinforce a trend found in neural signal processing across different species. Copyright © 2017 the American Physiological Society.

Effects of interaural time differences in fine structure and envelope on lateral discrimination in electric hearing.

PubMed

Majdak, Piotr; Laback, Bernhard; Baumgartner, Wolf-Dieter

2006-10-01

Bilateral cochlear implant (CI) listeners currently use stimulation strategies which encode interaural time differences (ITD) in the temporal envelope but which do not transmit ITD in the fine structure, due to the constant phase in the electric pulse train. To determine the utility of encoding ITD in the fine structure, ITD-based lateralization was investigated with four CI listeners and four normal hearing (NH) subjects listening to a simulation of electric stimulation. Lateralization discrimination was tested at different pulse rates for various combinations of independently controlled fine structure ITD and envelope ITD. Results for electric hearing show that the fine structure ITD had the strongest impact on lateralization at lower pulse rates, with significant effects for pulse rates up to 800 pulses per second. At higher pulse rates, lateralization discrimination depended solely on the envelope ITD. The data suggest that bilateral CI listeners benefit from transmitting fine structure ITD at lower pulse rates. However, there were strong interindividual differences: the better performing CI listeners performed comparably to the NH listeners.

Effects of rising angle on upstream blades and intermediate turbine duct

NASA Astrophysics Data System (ADS)

Liu, Jun; Wang, Pei; Du, Qiang; Liu, Guang; Zhu, Junqiang

2016-08-01

With the improvement of requirement, design and manufacture technology, aero-engines for the future are characterized by further reduction in fuel consumption, cost, but increment in propulsion efficiency, which leads to ultra-high bypass ratio. The intermediate turbine duct (ITD), which connects the high pressure turbine (HPT) with the low pressure turbine (LPT), has a critical impact on the overall performances of such future engines. Therefore, it becomes more and more urgent to master the design technique of aggressive, even super-aggressive ITDs. Over the last years, a lot of research works about the flow mechanism in the diffuser ducts were carried out. Many achievements were reported, but further investigation should be performed. With the aid of numerical method, this paper focuses on the change of performance and flow field of ITD, as well as nearby turbines, brought by rising angle (RA). Eight ITDs with the same area ratio and length, but different RAs ranges from 8 degrees to 45 degrees, are compared. According to the investigation, flow field, especially outlet Ma of swirl blade is influenced by RA under potential effect, which is advisable for designers to modify HPT rotor blades after changing ITD. In addition to that, low velocity area moves towards upstream until the first bend as RA increases, while pressure loss distribution at S2 stream surface shows that hub boundary layer is more sensitive to RA, and casing layer keeps almost constant. On the other hand, the overall total pressure loss could keep nearly equivalent among different RA cases, which implies the importance of optimization.

Modelling of human low frequency sound localization acuity demonstrates dominance of spatial variation of interaural time difference and suggests uniform just-noticeable differences in interaural time difference.

PubMed

Smith, Rosanna C G; Price, Stephen R

2014-01-01

Sound source localization is critical to animal survival and for identification of auditory objects. We investigated the acuity with which humans localize low frequency, pure tone sounds using timing differences between the ears. These small differences in time, known as interaural time differences or ITDs, are identified in a manner that allows localization acuity of around 1° at the midline. Acuity, a relative measure of localization ability, displays a non-linear variation as sound sources are positioned more laterally. All species studied localize sounds best at the midline and progressively worse as the sound is located out towards the side. To understand why sound localization displays this variation with azimuthal angle, we took a first-principles, systemic, analytical approach to model localization acuity. We calculated how ITDs vary with sound frequency, head size and sound source location for humans. This allowed us to model ITD variation for previously published experimental acuity data and determine the distribution of just-noticeable differences in ITD. Our results suggest that the best-fit model is one whereby just-noticeable differences in ITDs are identified with uniform or close to uniform sensitivity across the physiological range. We discuss how our results have several implications for neural ITD processing in different species as well as development of the auditory system.

The spatial unmasking of speech: evidence for within-channel processing of interaural time delay.

PubMed

Edmonds, Barrie A; Culling, John F

2005-05-01

Across-frequency processing by common interaural time delay (ITD) in spatial unmasking was investigated by measuring speech reception thresholds (SRTs) for high- and low-frequency bands of target speech presented against concurrent speech or a noise masker. Experiment 1 indicated that presenting one of these target bands with an ITD of +500 micros and the other with zero ITD (like the masker) provided some release from masking, but full binaural advantage was only measured when both target bands were given an ITD of + 500 micros. Experiment 2 showed that full binaural advantage could also be achieved when the high- and low-frequency bands were presented with ITDs of equal but opposite magnitude (+/- 500 micros). In experiment 3, the masker was also split into high- and low-frequency bands with ITDs of equal but opposite magnitude (+/-500 micros). The ITD of the low-frequency target band matched that of the high-frequency masking band and vice versa. SRTs indicated that, as long as the target and masker differed in ITD within each frequency band, full binaural advantage could be achieved. These results suggest that the mechanism underlying spatial unmasking exploits differences in ITD independently within each frequency channel.

Temporal Changes in FLT3-ITD Regulation of Stem Cell Self-Renewal and Leukemogenesis

DTIC Science & Technology

2015-09-01

whether FLT3-ITD depletes HSCs, expands restricted progenitors and promotes a myeloproliferative neoplasm during the adult, but not fetal stage of...goals: Aim 1: To test whether FLT3-ITD depletes HSCs, expands restricted progenitors and promotes a myeloproliferative neoplasm during the adult, but...progenitor pool and myeloproliferative neoplasms (MPN) were also evident in 14 day old FLT3-ITD mice but not fetal mice (Fig. 1F and not shown). FLT3-ITD

Spectral composition of concurrent noise affects neuronal sensitivity to interaural time differences of tones in the dorsal nucleus of the lateral lemniscus.

PubMed

Siveke, Ida; Leibold, Christian; Grothe, Benedikt

2007-11-01

We are regularly exposed to several concurrent sounds, producing a mixture of binaural cues. The neuronal mechanisms underlying the localization of concurrent sounds are not well understood. The major binaural cues for localizing low-frequency sounds in the horizontal plane are interaural time differences (ITDs). Auditory brain stem neurons encode ITDs by firing maximally in response to "favorable" ITDs and weakly or not at all in response to "unfavorable" ITDs. We recorded from ITD-sensitive neurons in the dorsal nucleus of the lateral lemniscus (DNLL) while presenting pure tones at different ITDs embedded in noise. We found that increasing levels of concurrent white noise suppressed the maximal response rate to tones with favorable ITDs and slightly enhanced the response rate to tones with unfavorable ITDs. Nevertheless, most of the neurons maintained ITD sensitivity to tones even for noise intensities equal to that of the tone. Using concurrent noise with a spectral composition in which the neuron's excitatory frequencies are omitted reduced the maximal response similar to that obtained with concurrent white noise. This finding indicates that the decrease of the maximal rate is mediated by suppressive cross-frequency interactions, which we also observed during monaural stimulation with additional white noise. In contrast, the enhancement of the firing rate to tones at unfavorable ITD might be due to early binaural interactions (e.g., at the level of the superior olive). A simple simulation corroborates this interpretation. Taken together, these findings suggest that the spectral composition of a concurrent sound strongly influences the spatial processing of ITD-sensitive DNLL neurons.

Effect of an inspiratory impedance threshold device on hemodynamics during conventional manual cardiopulmonary resuscitation.

PubMed

Pirrallo, Ronald G; Aufderheide, Tom P; Provo, Terry A; Lurie, Keith G

2005-07-01

In animals in cardiac arrest, an inspiratory impedance threshold device (ITD) has been shown to improve hemodynamics and neurologically intact survival. The objective of this study was to determine whether an ITD would improve blood pressure (BP) in patients receiving CPR for out-of-hospital cardiac arrest. This prospective, randomized, double-blind, intention-to-treat study was conducted in the Milwaukee, WI, emergency medical services (EMS) system. EMS personnel used an active (functional) or sham (non-functional) ITD on a tracheal tube on adults in cardiac arrest of presumed cardiac etiology. Care between groups was similar except for ITD type. Low dose epinephrine (1mg) was used per American Heart Association Guidelines. Femoral arterial BP (mmHg) was measured invasively during CPR. Mean+/-S.D. time from ITD placement to first invasive BP recording was approximately 14 min. Twelve patients were treated with a sham ITD versus 10 patients with an active ITD. Systolic BPs (mean+/-S.D.) [number of patients treated at given time point] at T = 0 (time of first arterial BP measurement), and T=2, 5 and 7 min were 85+/-29 [10], 85+/-23 [10], 85+/-16 [9] and 69+/-22 [8] in the group receiving an active ITD compared with 43+/-15 [12], 47+/-16 [12], 47+/-20 [9], and 52+/-23 [9] in subjects treated with a sham ITD, respectively (p < 0.01 for all times). Diastolic BPs at T = 0, 2, 5 and 7 min were 20+/-12, 21+/-13, 23+/-15 and 25+/-14 in the group receiving an active ITD compared with 15+/-9, 17+/-8, 17+/-9 and 19+/-8 in subjects treated with a sham ITD, respectively (p = NS for all times). No significant adverse device events were reported. Use of the active ITD was found to increase systolic pressures safely and significantly in patients in cardiac arrest compared with sham controls.

Maps of interaural delay in the owl's nucleus laminaris

PubMed Central

Shah, Sahil; McColgan, Thomas; Ashida, Go; Kuokkanen, Paula T.; Brill, Sandra; Kempter, Richard; Wagner, Hermann

2015-01-01

Axons from the nucleus magnocellularis form a presynaptic map of interaural time differences (ITDs) in the nucleus laminaris (NL). These inputs generate a field potential that varies systematically with recording position and can be used to measure the map of ITDs. In the barn owl, the representation of best ITD shifts with mediolateral position in NL, so as to form continuous, smoothly overlapping maps of ITD with iso-ITD contours that are not parallel to the NL border. Frontal space (0°) is, however, represented throughout and thus overrepresented with respect to the periphery. Measurements of presynaptic conduction delay, combined with a model of delay line conduction velocity, reveal that conduction delays can account for the mediolateral shifts in the map of ITD. PMID:26224776

RNA-based FLT3-ITD allelic ratio is associated with outcome and ex vivo response to FLT3 inhibitors in pediatric AML.

PubMed

Cucchi, David G J; Denys, Barbara; Kaspers, Gertjan J L; Janssen, Jeroen J W M; Ossenkoppele, Gert J; de Haas, Valérie; Zwaan, C Michel; van den Heuvel-Eibrink, Marry M; Philippé, Jan; Csikós, Tamás; Kwidama, Zinia; de Moerloose, Barbara; de Bont, Eveline S J M; Lissenberg-Witte, Birgit I; Zweegman, Sonja; Verwer, Femke; Vandepoele, Karl; Schuurhuis, Gerrit Jan; Sonneveld, Edwin; Cloos, Jacqueline

2018-05-31

Controversy exists whether internal tandem duplication of FMS-like tyrosine kinase 3 ( FLT3- internal tandem duplication [ITD]) allelic ratio (AR) and/or length of the ITD should be taken into account for risk stratification of pediatric acute myeloid leukemia (AML) and whether it should be measured on RNA or DNA. Moreover, the ITD status may be of relevance for selecting patients eligible for FLT3 inhibitors. Here, we included 172 pediatric AML patients, of whom 36 (21%) harbored FLT3 -ITD as determined on both RNA and DNA. Although there was a good correlation between both parameters AR spearman = 0.62 (95% confidence interval, 0.22-0.87) and ITDlength spearman = 0.98 (95% confidence interval, 0.90-1.00), only AR ≥ 0.5 and length ≥48 base pairs (bps) based on RNA measurements were significantly associated with overall survival (AR: P logrank = .008; ITDlength: P logrank = .011). In large ITDs (>156 bp on DNA) a remarkable 90-bp difference exists between DNA and RNA, including intron 14, which is spliced out in RNA. Ex vivo exposure (n = 30) to FLT3 inhibitors, in particular to the FLT3-specific inhibitor gilteritinib, showed that colony-forming capacity was significantly more reduced in FLT3 -ITD-AR ≥ 0.5 compared with ITD-AR-low and ITD - patient samples ( P < .001). RNA-based FLT3 -ITD measurements are recommended for risk stratification, and the relevance of AR regarding eligibility for FLT3-targeted therapy warrants further study. © 2018 by The American Society of Hematology.

Characterisation and Clinical Significance of FLT3-ITD and non-ITD in Acute Myeloid Leukaemia Patients in Kelantan, Northeast Peninsular Malaysia.

PubMed

Yunus, Noraini Mat; Johan, Muhammad Farid; Ali Nagi Al-Jamal, Hamid; Husin, Azlan; Hussein, Abdul Rahim; Hassan, Rosline

2015-01-01

Mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor gene may promote proliferation via activation of multiple signaling pathways. FLT3-internal tandem duplication (FLT3-ITD) is the most common gene alteration found in patients diagnosed with acute myeloid leukaemia (AML) and has been associated with poor prognosis. We performed mutational analysis of exons 14-15 and 20 of the FLT3 gene in 54 AML patients using PCR-CSGE (conformational sensitive gel electrophoresis) followed by sequencing analysis to characterise FLT3 mutations in adult patients diagnosed with AML at Hospital USM, Kelantan, Northeast Peninsular Malaysia. FLT3 exon 14-15 mutations were identified in 7 of 54 patients (13%) whereas no mutation was found in FLT3 exon 20. Six ITDs and one non-ITD mutation were found in exon 14 of the juxtamembrane (JM) domain of FLT3. FLT3-ITD mutations were associated with a significantly higher blast percentage (p-value=0.008) and white blood cell count (p-value=0.023) but there was no significant difference in median overall survival time for FLT3-ITD+/FLT3-ITD- within 2 years (p-value=0.374). The incidence of FLT3-ITD in AML patients in this particular region of Malaysia is low compared to the Western world and has a significant association with WBC and blast percentage.

Survivin Selectively Modulates Genes Deregulated in Human Leukemia Stem Cells

PubMed Central

Fukuda, Seiji; Abe, Mariko; Onishi, Chie; Taketani, Takeshi; Purevsuren, Jamiyan; Yamaguchi, Seiji; Conway, Edward M.; Pelus, Louis M.

2011-01-01

ITD-Flt3 mutations are detected in leukemia stem cells (LSCs) in acute myeloid leukemia (AML) patients. While antagonizing Survivin normalizes ITD-Flt3-induced acute leukemia, it also impairs hematopoietic stem cell (HSC) function, indicating that identification of differences in signaling pathways downstream of Survivin between LSC and HSC are crucial to develop selective Survivin-based therapeutic strategies for AML. Using a Survivin-deletion model, we identified 1,096 genes regulated by Survivin in ITD-Flt3-transformed c-kit+, Sca-1+, and lineageneg (KSL) cells, of which 137 are deregulated in human LSC. Of the 137, 124 genes were regulated by Survivin exclusively in ITD-Flt3+ KSL cells but not in normal CD34neg KSL cells. Survivin-regulated genes in LSC connect through a network associated with the epidermal growth factor receptor signaling pathway and falls into various functional categories independent of effects on apoptosis. Pathways downstream of Survivin in LSC that are distinct from HSC can be potentially targeted for selective anti-LSC therapy. PMID:21253548

Allogeneic Stem Cell Transplantation Improves Survival in Patients with Acute Myeloid Leukemia Characterized by a High Allelic Ratio of Mutant FLT3-ITD.

PubMed

Ho, Anthony D; Schetelig, Johannes; Bochtler, Tilmann; Schaich, Markus; Schäfer-Eckart, Kerstin; Hänel, Mathias; Rösler, Wolf; Einsele, Hermann; Kaufmann, Martin; Serve, Hubert; Berdel, Wolfgang E; Stelljes, Matthias; Mayer, Jiri; Reichle, Albrecht; Baldus, Claudia D; Schmitz, Norbert; Kramer, Michael; Röllig, Christoph; Bornhäuser, Martin; Thiede, Christian; Ehninger, Gerhard

2016-03-01

Allogeneic hematopoietic cell transplantation (alloHCT) as a postremission therapy in patients with FLT3-ITD-positive intermediate-risk acute myeloid leukemia (AML) remains controversial. FLT3-ITD mutations are heterogeneous with respect to allelic ratio, location, and length of the insertion, with a high mutant-to-wild-type ratio consistently associated with inferior prognosis. We retrospectively analyzed the role of alloHCT in first remission in relationship to the allelic ratio and presence or absence of nucleophosmin 1 mutations (NPM1) in the Study Alliance Leukemia AML2003 trial. FLT3-ITD mutations were detected in 209 patients and concomitant NPM1 mutations in 148 patients. Applying a predefined cutoff ratio of .8, AML was grouped into high- and low-ratio FLT3-ITD AML (HR(FLT3-ITD) and LR(FLT3-ITD)). Sixty-one patients (29%) were transplanted in first remission. Overall survival (OS) (HR, .3; 95% CI, .16 to .7; P = .004) and event-free survival (EFS) (HR, .4; 95% CI, .16 to .9; P = .02) were significantly increased in patients with HR(FLT3-ITD) AML who received alloHCT as consolidation treatment compared with patients who received consolidation chemotherapy. Patients with LR(FLT3-ITD) AML and wild-type NPM1 who received alloHCT in first remission had increased OS (HR, .3; 95% CI, .1 to .8; P = .02) and EFS (HR, .2; 95% CI, .1 to .8; P = .02), whereas alloHCT in first remission did not have a significant impact on OS and EFS in patients with LR(FLT3-ITD) AML and concomitant NPM1 mutation. In conclusion, our results provide additional evidence that alloHCT in first remission improves EFS and OS in patients with HR(FLT3-ITD) AML and in patients with LR(FLT3-ITD) AML and wild-type NPM1. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Temporal Changes in FLT3 ITD Regulation of Stem Cell Self Renewal and Leukemogenesis

DTIC Science & Technology

2016-11-01

JAM is a 661   scholar of the Child Health Research Center for Excellence in Developmental 662   Biology at Washington University (K12-HD076224...SUPPLEMENTARY NOTES 14. ABSTRACT My goal is to understand how mechanisms that regulate normal hematopoietic development can also influence the mutation...pathways) in fetal, neonatal and adult progenitors. STAT5 was activated by FLT3-ITD at all stages of development , but MAPK was activated only in post

How sensitivity to ongoing interaural temporal disparities is affected by manipulations of temporal features of the envelopes of high-frequency stimuli

PubMed Central

Bernstein, Leslie R.; Trahiotis, Constantine

2009-01-01

This study addressed how manipulating certain aspects of the envelopes of high-frequency stimuli affects sensitivity to envelope-based interaural temporal disparities (ITDs). Listener’s threshold ITDs were measured using an adaptive two-alternative paradigm employing “raised-sine” stimuli [John, M. S., et al. (2002). Ear Hear. 23, 106–117] which permit independent variation in their modulation frequency, modulation depth, and modulation exponent. Threshold ITDs were measured while manipulating modulation exponent for stimuli having modulation frequencies between 32 and 256 Hz. The results indicated that graded increases in the exponent led to graded decreases in envelope-based threshold ITDs. Threshold ITDs were also measured while parametrically varying modulation exponent and modulation depth. Overall, threshold ITDs decreased with increases in the modulation depth. Unexpectedly, increases in the exponent of the raised-sine led to especially large decreases in threshold ITD when the modulation depth was low. An interaural correlation-based model was generally able to capture changes in threshold ITD stemming from changes in the exponent, depth of modulation, and frequency of modulation of the raised-sine stimuli. The model (and several variations of it), however, could not account for the unexpected interaction between the value of raised-sine exponent and its modulation depth. PMID:19425666

Sensitivity to binaural timing in bilateral cochlear implant users.

PubMed

van Hoesel, Richard J M

2007-04-01

Various measures of binaural timing sensitivity were made in three bilateral cochlear implant users, who had demonstrated moderate-to-good interaural time delay (ITD) sensitivity at 100 pulses-per-second (pps). Overall, ITD thresholds increased at higher pulse rates, lower levels, and shorter durations, although intersubject differences were evident. Monaural rate-discrimination thresholds, using the same stimulation parameters, showed more substantial elevation than ITDs with increased rate. ITD sensitivity with 6000 pps stimuli, amplitude-modulated at 100 Hz, was similar to that with unmodulated pulse trains at 100 pps, but at 200 and 300 Hz performance was poorer than with unmodulated signals. Measures of sensitivity to binaural beats with unmodulated pulse-trains showed that all three subjects could use time-varying ITD cues at 100 pps, but not 300 pps, even though static ITD sensitivity was relatively unaffected over that range. The difference between static and dynamic ITD thresholds is discussed in terms of relative contributions from initial and later arriving cues, which was further examined in an experiment using two-pulse stimuli as a function of interpulse separation. In agreement with the binaural-beat data, findings from that experiment showed poor discrimination of ITDs on the second pulse when the interval between pulses was reduced to a few milliseconds.

Extraction of Inter-Aural Time Differences Using a Spiking Neuron Network Model of the Medial Superior Olive.

PubMed

Encke, Jörg; Hemmert, Werner

2018-01-01

The mammalian auditory system is able to extract temporal and spectral features from sound signals at the two ears. One important cue for localization of low-frequency sound sources in the horizontal plane are inter-aural time differences (ITDs) which are first analyzed in the medial superior olive (MSO) in the brainstem. Neural recordings of ITD tuning curves at various stages along the auditory pathway suggest that ITDs in the mammalian brainstem are not represented in form of a Jeffress-type place code. An alternative is the hemispheric opponent-channel code, according to which ITDs are encoded as the difference in the responses of the MSO nuclei in the two hemispheres. In this study, we present a physiologically-plausible, spiking neuron network model of the mammalian MSO circuit and apply two different methods of extracting ITDs from arbitrary sound signals. The network model is driven by a functional model of the auditory periphery and physiological models of the cochlear nucleus and the MSO. Using a linear opponent-channel decoder, we show that the network is able to detect changes in ITD with a precision down to 10 μs and that the sensitivity of the decoder depends on the slope of the ITD-rate functions. A second approach uses an artificial neuronal network to predict ITDs directly from the spiking output of the MSO and ANF model. Using this predictor, we show that the MSO-network is able to reliably encode static and time-dependent ITDs over a large frequency range, also for complex signals like speech.

Binaural sensitivity in children who use bilateral cochlear implants.

PubMed

Ehlers, Erica; Goupell, Matthew J; Zheng, Yi; Godar, Shelly P; Litovsky, Ruth Y

2017-06-01

Children who are deaf and receive bilateral cochlear implants (BiCIs) perform better on spatial hearing tasks using bilateral rather than unilateral inputs; however, they underperform relative to normal-hearing (NH) peers. This gap in performance is multi-factorial, including the inability of speech processors to reliably deliver binaural cues. Although much is known regarding binaural sensitivity of adults with BiCIs, less is known about how the development of binaural sensitivity in children with BiCIs compared to NH children. Sixteen children (ages 9-17 years) were tested using synchronized research processors. Interaural time differences and interaural level differences (ITDs and ILDs, respectively) were presented to pairs of pitch-matched electrodes. Stimuli were 300-ms, 100-pulses-per-second, constant-amplitude pulse trains. In the first and second experiments, discrimination of interaural cues (either ITDs or ILDs) was measured using a two-interval left/right task. In the third experiment, subjects reported the perceived intracranial position of ITDs and ILDs in a lateralization task. All children demonstrated sensitivity to ILDs, possibly due to monaural level cues. Children who were born deaf had weak or absent sensitivity to ITDs; in contrast, ITD sensitivity was noted in children with previous exposure to acoustic hearing. Therefore, factors such as auditory deprivation, in particular, lack of early exposure to consistent timing differences between the ears, may delay the maturation of binaural circuits and cause insensitivity to binaural differences.

Intratympanic steroids injection is effective for the treatment of drop attacks with Ménière's disease and delayed endolymphatic hydrops

PubMed Central

Liu, Bo; Leng, Yangming; Zhou, Renhong; Liu, Jingjing; Liu, Dongdong; Zhang, Su-Lin; Kong, Wei-Jia

2016-01-01

Abstract Drop attack (DA) associated with Ménière's disease (MD) and delayed endolymphatic hydrops (DEH) is not common and may cause life-threatening clinical problems. The intratympanic dexamethasone (ITD) is one of primary treatments for MD or DEH. Our study investigated the effect of ITD on the DA associated with endolymphatic hydrops (EH). We retrospectively reviewed 10 patients with MD- and DEH-associated DA between January 2009 and December 2013 in Outpatient Department of Otolaryngology, Union Hospital, Wuhan, China. Among them, 7 patients (5 cases with MD, 2 cases of DEH) received ITD (4 times, on weekly basis). Further repeated ITD courses or intratympanic gentamicin (ITG) were given if the vertigo was not satisfactorily controlled. The number of DA and status of vertigo control after intratympanic injection were evaluated. After a follow-up study lasting from 19 to 35 months, DA in 5 cases (71.4%) disappeared after initial ITD course. In 2 cases, DA was altogether controlled after an additional intratympanic injection (repeated ITD or/and ITG). This study showed that ITD promises to be a first-line conservative treatment for MD- or DEH-related DA since the steroid possesses no inner-ear toxicity. Furthermore, for MD- or DEH-related DA refractory to ITD, ITG can be an effective alternative. PMID:28033296

Performance Analysis of IIUM Wireless Campus Network

NASA Astrophysics Data System (ADS)

Abd Latif, Suhaimi; Masud, Mosharrof H.; Anwar, Farhat

2013-12-01

International Islamic University Malaysia (IIUM) is one of the leading universities in the world in terms of quality of education that has been achieved due to providing numerous facilities including wireless services to every enrolled student. The quality of this wireless service is controlled and monitored by Information Technology Division (ITD), an ISO standardized organization under the university. This paper aims to investigate the constraints of wireless campus network of IIUM. It evaluates the performance of the IIUM wireless campus network in terms of delay, throughput and jitter. QualNet 5.2 simulator tool has employed to measure these performances of IIUM wireless campus network. The observation from the simulation result could be one of the influencing factors in improving wireless services for ITD and further improvement.

Detection of Interaural Time Differences in the Alligator

PubMed Central

Carr, Catherine E.; Soares, Daphne; Smolders, Jean; Simon, Jonathan Z.

2011-01-01

The auditory systems of birds and mammals use timing information from each ear to detect interaural time difference (ITD). To determine whether the Jeffress-type algorithms that underlie sensitivity to ITD in birds are an evolutionarily stable strategy, we recorded from the auditory nuclei of crocodilians, who are the sister group to the birds. In alligators, precisely timed spikes in the first-order nucleus magnocellularis (NM) encode the timing of sounds, and NM neurons project to neurons in the nucleus laminaris (NL) that detect interaural time differences. In vivo recordings from NL neurons show that the arrival time of phase-locked spikes differs between the ipsilateral and contralateral inputs. When this disparity is nullified by their best ITD, the neurons respond maximally. Thus NL neurons act as coincidence detectors. A biologically detailed model of NL with alligator parameters discriminated ITDs up to 1 kHz. The range of best ITDs represented in NL was much larger than in birds, however, and extended from 0 to 1000 μs contralateral, with a median ITD of 450 μs. Thus, crocodilians and birds employ similar algorithms for ITD detection, although crocodilians have larger heads. PMID:19553438

Effectiveness of Interaural Delays Alone as Cues During Dynamic Sound Localization

NASA Technical Reports Server (NTRS)

Wenzel, Elizabeth M.; Null, Cynthia H. (Technical Monitor)

1996-01-01

The contribution of interaural time differences (ITDs) to the localization of virtual sound sources with and without head motion was examined. Listeners estimated the apparent azimuth, elevation and distance of virtual sources presented over headphones. Stimuli (3 sec., white noise) were synthesized from minimum-phase representations of nonindividualized head-related transfer functions (HRTFs); binaural magnitude spectra were derived from the minimum phase estimates and ITDs were represented as a pure delay. During dynamic conditions, listeners were encouraged to move their heads; head position was tracked and stimuli were synthesized in real time using a Convolvotron to simulate a stationary external sound source. Two synthesis conditions were tested: (1) both interaural level differences (ILDs) and ITDs correctly correlated with source location and head motion, (2) ITDs correct, no ILDs (flat magnitude spectrum). Head movements reduced azimuth confusions primarily when interaural cues were correctly correlated, although a smaller effect was also seen for ITDs alone. Externalization was generally poor for ITD-only conditions and was enhanced by head motion only for normal HRTFs. Overall the data suggest that, while ITDs alone can provide a significant cue for azimuth, the errors most commonly associated with virtual sources are reduced by location-dependent magnitude cues.

76 FR 46853 - International Business Machines Corporation, ITD Business Unit, Division 7, E-mail and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-03

...] International Business Machines Corporation, ITD Business Unit, Division 7, E-mail and Collaboration Group... Business Machines Corporation (IBM), ITD Business Unit, Division 7, E- mail and Collaboration Group... Business Unit, Division 7, E-mail and Collaboration [[Page 46854

Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group.

PubMed

Manara, E; Basso, G; Zampini, M; Buldini, B; Tregnago, C; Rondelli, R; Masetti, R; Bisio, V; Frison, M; Polato, K; Cazzaniga, G; Menna, G; Fagioli, F; Merli, P; Biondi, A; Pession, A; Locatelli, F; Pigazzi, M

2017-01-01

Recurrent molecular markers have been routinely used in acute myeloid leukemia (AML) for risk assessment at diagnosis, whereas their post-induction monitoring still represents a debated issue. We evaluated the prognostic value and biological impact of minimal residual disease (MRD) and of the allelic ratio (AR) of FLT3-internal-tandem duplication (ITD) in childhood AML. We retrospectively screened 494 children with de novo AML for FLT3-ITD mutation, identifying 54 harboring the mutation; 51% of them presented high ITD-AR at diagnosis and had worse event-free survival (EFS, 19.2 versus 63.5% for low ITD-AR, <0.05). Forty-one percent of children with high levels of MRD after the 1st induction course, measured by a patient-specific real-time-PCR, had worse EFS (22.2 versus 59.4% in low-MRD patients, P<0.05). Next, we correlated these parameters with gene expression, showing that patients with high ITD-AR or persistent MRD had characteristic expression profiles with deregulated genes involved in methylation and acetylation. Moreover, patients with high CyclinA1 expression presented an unfavorable EFS (20.3 versus 51.2% in low CyclinA1 group, P<0.01). Our results suggest that ITD-AR levels and molecular MRD should be considered in planning clinical management of FLT3-ITD patients. Different transcriptional activation of epigenetic and oncogenic profiles may explain variability in outcome among these patients, for whom novel therapeutic approaches are desirable.

Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

PubMed Central

Doshi, Kshama A.; Trotta, Rossana; Natarajan, Karthika; Rassool, Feyruz V.; Tron, Adriana E.; Huszar, Dennis; Perrotti, Danilo; Baer, Maria R.

2016-01-01

Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD. PMID:27374090

Dual sensitivity of inferior colliculus neurons to ITD in the envelopes of high-frequency sounds: experimental and modeling study

PubMed Central

Wang, Le; Devore, Sasha; Delgutte, Bertrand

2013-01-01

Human listeners are sensitive to interaural time differences (ITDs) in the envelopes of sounds, which can serve as a cue for sound localization. Many high-frequency neurons in the mammalian inferior colliculus (IC) are sensitive to envelope-ITDs of sinusoidally amplitude-modulated (SAM) sounds. Typically, envelope-ITD-sensitive IC neurons exhibit either peak-type sensitivity, discharging maximally at the same delay across frequencies, or trough-type sensitivity, discharging minimally at the same delay across frequencies, consistent with responses observed at the primary site of binaural interaction in the medial and lateral superior olives (MSO and LSO), respectively. However, some high-frequency IC neurons exhibit dual types of envelope-ITD sensitivity in their responses to SAM tones, that is, they exhibit peak-type sensitivity at some modulation frequencies and trough-type sensitivity at other frequencies. Here we show that high-frequency IC neurons in the unanesthetized rabbit can also exhibit dual types of envelope-ITD sensitivity in their responses to SAM noise. Such complex responses to SAM stimuli could be achieved by convergent inputs from MSO and LSO onto single IC neurons. We test this hypothesis by implementing a physiologically explicit, computational model of the binaural pathway. Specifically, we examined envelope-ITD sensitivity of a simple model IC neuron that receives convergent inputs from MSO and LSO model neurons. We show that dual envelope-ITD sensitivity emerges in the IC when convergent MSO and LSO inputs are differentially tuned for modulation frequency. PMID:24155013

A method to enhance the use of interaural time differences for cochlear implants in reverberant environments

PubMed Central

Monaghan, Jessica J. M.; Seeber, Bernhard U.

2017-01-01

The ability of normal-hearing (NH) listeners to exploit interaural time difference (ITD) cues conveyed in the modulated envelopes of high-frequency sounds is poor compared to ITD cues transmitted in the temporal fine structure at low frequencies. Sensitivity to envelope ITDs is further degraded when envelopes become less steep, when modulation depth is reduced, and when envelopes become less similar between the ears, common factors when listening in reverberant environments. The vulnerability of envelope ITDs is particularly problematic for cochlear implant (CI) users, as they rely on information conveyed by slowly varying amplitude envelopes. Here, an approach to improve access to envelope ITDs for CIs is described in which, rather than attempting to reduce reverberation, the perceptual saliency of cues relating to the source is increased by selectively sharpening peaks in the amplitude envelope judged to contain reliable ITDs. Performance of the algorithm with room reverberation was assessed through simulating listening with bilateral CIs in headphone experiments with NH listeners. Relative to simulated standard CI processing, stimuli processed with the algorithm generated lower ITD discrimination thresholds and increased extents of laterality. Depending on parameterization, intelligibility was unchanged or somewhat reduced. The algorithm has the potential to improve spatial listening with CIs. PMID:27586742

Noise reduction of coincidence detector output by the inferior colliculus of the barn owl.

PubMed

Christianson, G Björn; Peña, José Luis

2006-05-31

A recurring theme in theoretical work is that integration over populations of similarly tuned neurons can reduce neural noise. However, there are relatively few demonstrations of an explicit noise reduction mechanism in a neural network. Here we demonstrate that the brainstem of the barn owl includes a stage of processing apparently devoted to increasing the signal-to-noise ratio in the encoding of the interaural time difference (ITD), one of two primary binaural cues used to compute the position of a sound source in space. In the barn owl, the ITD is processed in a dedicated neural pathway that terminates at the core of the inferior colliculus (ICcc). The actual locus of the computation of the ITD is before ICcc in the nucleus laminaris (NL), and ICcc receives no inputs carrying information that did not originate in NL. Unlike in NL, the rate-ITD functions of ICcc neurons require as little as a single stimulus presentation per ITD to show coherent ITD tuning. ICcc neurons also displayed a greater dynamic range with a maximal difference in ITD response rates approximately double that seen in NL. These results indicate that ICcc neurons perform a computation functionally analogous to averaging across a population of similarly tuned NL neurons.

A noncanonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia.

PubMed

Shanmugam, Rajasubramaniam; Gade, Padmaja; Wilson-Weekes, Annique; Sayar, Hamid; Suvannasankha, Attaya; Goswami, Chirayu; Li, Lang; Gupta, Sushil; Cardoso, Angelo A; Baghdadi, Tareq Al; Sargent, Katie J; Cripe, Larry D; Kalvakolanu, Dhananjaya V; Boswell, H Scott

2012-01-15

Death-associated protein kinase 1 (DAPK1), a tumor suppressor, is a rate-limiting effector in an endoplasmic reticulum (ER) stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of acute myeloid leukemia (AML) with poor prognosis, which lacked ER stress-induced apoptosis. Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB-and c-Jun-responsive genes, was studied. RNA interference knockdown studies were carried out in an Flt3ITD(+) cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were carried out to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. AMLs characterized by normal karyotype with Flt3ITD were found to have 10- to 100-fold lower DAPK1 transcripts normalized to the expression of c-Jun, a transcriptional activator of DAPK1, as compared with a heterogeneous cytogenetic category. In addition, Meis1, a c-Jun-responsive adverse AML prognostic gene signature was measured as control. These Flt3ITD(+) AMLs overexpress relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter together with histone deacetylase 2 (HDAC2) and HDAC6 in the Flt3ITD(+) human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NF-κB-inducing kinase (NIK), de-repressed DAPK1. DAPK1-repressed primary Flt3ITD(+) AMLs had selective nuclear activation of p52NF-κB. Flt3ITD promotes a noncanonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD(+) AML. ©2011 AACR.

A non-canonical Flt3ITD/NF-κB signaling pathway represses DAPK1 in acute myeloid leukemia (AML)

PubMed Central

Shanmugam, Rajasubramaniam; Sayar, Hamid; Suvannasankha, Attaya; Goswami, Chirayu; Li, Lang; Gupta, Sushil; Cardoso, Angelo A.; Baghdadi, Tareq Al; Sargent, Katie J.; Cripe, Larry D.; Kalvakolanu, Dhananjaya V.; Boswell, H. Scott

2014-01-01

Purpose DAPK1, a tumor suppressor, is a rate-limiting effector in an ER stress-dependent apoptotic pathway. Its expression is epigenetically suppressed in several tumors. A mechanistic basis for epigenetic/transcriptional repression of DAPK1 was investigated in certain forms of AML with poor prognosis, which lacked ER stress-induced apoptosis. Experimental Design Heterogeneous primary AMLs were screened to identify a subgroup with Flt3ITD in which repression of DAPK1, among NF-κB- and c- jun-responsive genes, was studied. RNAi knockdown studies were performed in Flt3ITD+ve cell line, MV-4-11, to establish genetic epistasis in the pathway Flt3ITD-TAK1-DAPK1 repression, and chromatin immunoprecipitations were performed to identify proximate effector proteins, including TAK1-activated p52NF-κB, at the DAPK1 locus. Results AMLs characterized by normal karyotype with Flt3ITD were found to have 10-100-fold lower DAPK1 transcripts normalized to the expression of c-jun, a transcriptional activator of DAPK1, as compared to a heterogeneous cytogenetic category. Meis1, a c-jun-responsive adverse AML prognostic gene signature was also measured as control. These Flt3ITD+ve AMLs over-express relB, a transcriptional repressor, which forms active heterodimers with p52NF-κB. Chromatin immunoprecipitation assays identified p52NF-κB binding to the DAPK1 promoter along with HDAC2 and HDAC6 in the Flt3ITD+ve human AML cell line MV-4-11. Knockdown of p52NF-κB or its upstream regulator, NIK, de-repressed DAPK1. DAPK1-repressed primary Flt3ITD+ve AMLs had selective nuclear activation of p52NF-κB. Conclusions Flt3ITD promotes a non-canonical pathway via TAK1 and p52NF-κB to suppress DAPK1 in association with HDACs, which explains DAPK1 repression in Flt3ITD+ve AML. PMID:22096027

Reperfusion injury protection during Basic Life Support improves circulation and survival outcomes in a porcine model of prolonged cardiac arrest.

PubMed

Debaty, Guillaume; Lurie, Keith; Metzger, Anja; Lick, Michael; Bartos, Jason A; Rees, Jennifer N; McKnite, Scott; Puertas, Laura; Pepe, Paul; Fowler, Raymond; Yannopoulos, Demetris

2016-08-01

Ischemic postconditioning (PC) using three intentional pauses at the start of cardiopulmonary resuscitation (CPR) improves outcomes after cardiac arrest in pigs when epinephrine (epi) is used before defibrillation. We hypothesized PC, performed during basic life support (BLS) in the absence of epinephrine, would reduce reperfusion injury and enhance 24h functional recovery. Prospective animal investigation. Animal laboratory Female farm pigs (n=46, 39±1kg). Protocol A: After 12min of ventricular fibrillation (VF), 28 pigs were randomized to four groups: (A) Standard CPR (SCPR), (B) active compression-decompression CPR with an impedance threshold device (ACD-ITD), (C) SCPR+PC (SCPR+PC) and (D) ACD-ITD CPR+PC. Protocol B: After 15min of VF, 18 pigs were randomized to ACD-ITD CPR or ACD-ITD+PC. The BLS duration was 2.75min in Protocol A and 5min in Protocol B. Following BLS, up to three shocks were delivered. Without return of spontaneous circulation (ROSC), CPR was resumed and epi (0.5mg) and defibrillation delivered. The primary end point was survival without major adverse events. Hemodynamic parameters and left ventricular ejection fraction (LVEF) were also measured. Data are presented as mean±SEM. Protocol A: ACD-ITD+PC (group D) improved coronary perfusion pressure after 3min of BLS versus the three other groups (28±6, 35±7, 23±5 and 47±7 for groups A, B, C, D respectively, p=0.05). There were no significant differences in 24h survival between groups. LVEF 4h post ROSC was significantly higher with ACD-ITD+PC vs ACD-ITD alone (52.5±3% vs. 37.5±6.6%, p=0.045). Survival rates were significantly higher with ACD-ITD+PC vs. ACD-ITD alone (p=0.027). BLS using ACD-ITD+PC reduced post resuscitation cardiac dysfunction and improved functional recovery after prolonged untreated VF in pigs. 12-11. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Attentional Bias to Negative Affect Moderates Negative Affect’s Relationship with Smoking Abstinence

PubMed Central

Etcheverry, Paul E.; Waters, Andrew J.; Lam, Cho; Correa-Fernandez, Virmarie; Vidrine, Jennifer Irvin; Cinciripini, Paul M.; Wetter, David W.

2016-01-01

Objective To examine whether initial orienting (IO) and inability to disengage attention (ITD) from negative affective stimuli moderate the association of negative affect with smoking abstinence during a quit attempt. Methods Data were from a longitudinal cohort study of smoking cessation (N=424). A negative affect modified Stroop was administered one week before and on quit day to measure IO and ITD. Ecological Momentary Assessments were used to create negative affect intercepts and linear slopes for the week before quitting and on quit day. Quit day and long-term abstinence measures were collected. Results Continuation ratio (CR) logit model analyses found significant interactions of pre-quit negative affect slope with pre-quit ITD [OR = .738(.57, .96), p= .02] and quit day negative affect intercept with quit day ITD [OR = .62(.41, 950), p= .03] predicting abstinence. The interaction of pre-quit negative affect intercept and pre-quit IO predicting quit day abstinence was significant [OR = 1.42(1.06, 1.90), p= .02], as was the interaction of quit day negative affect slope and quit day IO predicting long-term abstinence [OR = 1.45(1.02, 2.08), p= .04]. Conclusions The hypothesis that the association of negative affect with smoking abstinence would be moderated by ITD was generally supported. Among individuals with high ITD, negative affect was inversely related to abstinence, but unrelated to abstinence among individuals with lower levels of ITD. Unexpectedly, among individuals with low IO negative affect was inversely related to abstinence, but unrelated to abstinence among individuals with higher levels of ITD. PMID:27505211

Localization and interaural time difference (ITD) thresholds for cochlear implant recipients with preserved acoustic hearing in the implanted ear

PubMed Central

Gifford, René H.; Grantham, D. Wesley; Sheffield, Sterling W.; Davis, Timothy J.; Dwyer, Robert; Dorman, Michael F.

2014-01-01

The purpose of this study was to investigate horizontal plane localization and interaural time difference (ITD) thresholds for 14 adult cochlear implant recipients with hearing preservation in the implanted ear. Localization to broadband noise was assessed in an anechoic chamber with a 33-loudspeaker array extending from −90 to +90°. Three listening conditions were tested including bilateral hearing aids, bimodal (implant + contralateral hearing aid) and best aided (implant + bilateral hearing aids). ITD thresholds were assessed, under headphones, for low-frequency stimuli including a 250-Hz tone and bandpass noise (100–900 Hz). Localization, in overall rms error, was significantly poorer in the bimodal condition (mean: 60.2°) as compared to both bilateral hearing aids (mean: 46.1°) and the best-aided condition (mean: 43.4°). ITD thresholds were assessed for the same 14 adult implant recipients as well as 5 normal-hearing adults. ITD thresholds were highly variable across the implant recipients ranging from the range of normal to ITDs not present in real-world listening environments (range: 43 to over 1600 μs). ITD thresholds were significantly correlated with localization, the degree of interaural asymmetry in low-frequency hearing, and the degree of hearing preservation related benefit in the speech reception threshold (SRT). These data suggest that implant recipients with hearing preservation in the implanted ear have access to binaural cues and that the sensitivity to ITDs is significantly correlated with localization and degree of preserved hearing in the implanted ear. PMID:24607490

Attentional bias to negative affect moderates negative affect's relationship with smoking abstinence.

PubMed

Etcheverry, Paul E; Waters, Andrew J; Lam, Cho; Correa-Fernandez, Virmarie; Vidrine, Jennifer Irvin; Cinciripini, Paul M; Wetter, David W

2016-08-01

To examine whether initial orienting (IO) and inability to disengage (ITD) attention from negative affective stimuli moderate the association of negative affect with smoking abstinence during a quit attempt. Data were from a longitudinal cohort study of smoking cessation (N = 424). A negative affect modified Stroop task was administered 1 week before and on quit day to measure IO and ITD. Ecological Momentary Assessments were used to create negative affect intercepts and linear slopes for the week before quitting and on quit day. Quit day and long-term abstinence measures were collected. Continuation ratio logit model analyses found significant interactions for prequit negative affect slope with prequit ITD, odds ratio (OR) = 0.738 (0.57, 0.96), p = .02, and for quit day negative affect intercept with quit day ITD, OR = 0.62 (0.41, 950), p = .03, predicting abstinence. The Prequit Negative Affect Intercept × Prequit IO interaction predicting quit day abstinence was significant, OR = 1.42 (1.06, 1.90), p = .02, as was the Quit Day Negative Affect Slope × Quit Day IO interaction predicting long-term abstinence, OR = 1.45 (1.02, 2.08), p = .04. The hypothesis that the association of negative affect with smoking abstinence would be moderated by ITD was generally supported. Among individuals with high ITD, negative affect was inversely related to abstinence, but unrelated to abstinence among individuals with lower levels of ITD. Unexpectedly, among individuals with low IO, negative affect was inversely related to abstinence, but unrelated to abstinence among individuals with higher levels of ITD. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Prevalence of exon 11 internal tandem duplications in the C-KIT proto-oncogene in Australian canine mast cell tumours.

PubMed

Tamlin, V S; Kessell, A E; Mccoy, R J; Dobson, E C; Smith, T S; Hebart, M; Brown, L; Mitrovic, D; Peaston, A E

2017-10-01

To measure the prevalence of internal tandem duplications (ITDs) in exon 11 of the proto-oncogene C-KIT in a sample of Australian cutaneous canine mast cell tumours (MCTs) drawn from general practice and to evaluate relationships between tumour mutation status and prognostic factors including signalment, tumour histological grade, tumour anatomical location and tumour size. C-KIT exon 11 ITDs were detected by PCR in DNA extracted from formalin-fixed, paraffin-embedded canine MCTs sourced from three veterinary diagnostic laboratories in Adelaide and Melbourne. Tumours were graded according to two different systems (Patnaik and Kiupel systems) by board-certified anatomical pathologists blinded to the PCR results. Relationships between tumour mutation status and prognostic factors were evaluated using a generalised binary logistic regression analysis. ITDs were identified in 13 of 74 cutaneous canine MCT samples, giving an overall prevalence of 17.6% (95% confidence interval: 8.9-26.2%). ITDs were detected in 10 of 18 Patnaik grade III MCTs (55.6%) and 11 of 22 Kiupel high-grade MCTs (50%). Wald chi-square analysis revealed that detection of tumour ITDs was significantly associated with both Patnaik's and Kiupel's histologic grading systems (each: P < 0.001). The presence of the ITDs in MCTs was not associated with signalment, tumour anatomical location or tumour size. The prevalence of C-KIT exon 11 ITDs in Australian canine MCTs is similar to the prevalence in overseas canine populations (overall prevalence in Australia approximately 18%). ITDs were more frequently identified in higher grade MCTs. © 2017 Australian Veterinary Association.

Localization and interaural time difference (ITD) thresholds for cochlear implant recipients with preserved acoustic hearing in the implanted ear.

PubMed

Gifford, René H; Grantham, D Wesley; Sheffield, Sterling W; Davis, Timothy J; Dwyer, Robert; Dorman, Michael F

2014-06-01

The purpose of this study was to investigate horizontal plane localization and interaural time difference (ITD) thresholds for 14 adult cochlear implant recipients with hearing preservation in the implanted ear. Localization to broadband noise was assessed in an anechoic chamber with a 33-loudspeaker array extending from -90 to +90°. Three listening conditions were tested including bilateral hearing aids, bimodal (implant + contralateral hearing aid) and best aided (implant + bilateral hearing aids). ITD thresholds were assessed, under headphones, for low-frequency stimuli including a 250-Hz tone and bandpass noise (100-900 Hz). Localization, in overall rms error, was significantly poorer in the bimodal condition (mean: 60.2°) as compared to both bilateral hearing aids (mean: 46.1°) and the best-aided condition (mean: 43.4°). ITD thresholds were assessed for the same 14 adult implant recipients as well as 5 normal-hearing adults. ITD thresholds were highly variable across the implant recipients ranging from the range of normal to ITDs not present in real-world listening environments (range: 43 to over 1600 μs). ITD thresholds were significantly correlated with localization, the degree of interaural asymmetry in low-frequency hearing, and the degree of hearing preservation related benefit in the speech reception threshold (SRT). These data suggest that implant recipients with hearing preservation in the implanted ear have access to binaural cues and that the sensitivity to ITDs is significantly correlated with localization and degree of preserved hearing in the implanted ear. Copyright © 2014. Published by Elsevier B.V.

Localization of sound in rooms. V. Binaural coherence and human sensitivity to interaural time differences in noise

PubMed Central

Rakerd, Brad; Hartmann, William M.

2010-01-01

Binaural recordings of noise in rooms were used to determine the relationship between binaural coherence and the effectiveness of the interaural time difference (ITD) as a cue for human sound localization. Experiments showed a strong, monotonic relationship between the coherence and a listener’s ability to discriminate values of ITD. The relationship was found to be independent of other, widely varying acoustical properties of the rooms. However, the relationship varied dramatically with noise band center frequency. The ability to discriminate small ITD changes was greatest for a mid-frequency band. To achieve sensitivity comparable to mid-band, the binaural coherence had to be much larger at high frequency, where waveform ITD cues are imperceptible, and also at low frequency, where the binaural coherence in a room is necessarily large. Rivalry experiments with opposing interaural level differences (ILDs) found that the trading ratio between ITD and ILD increasingly favored the ILD as coherence decreased, suggesting that the perceptual weight of the ITD is decreased by increased reflections in rooms. PMID:21110600

FLT3-ITD confers resistance to the PI3K/Akt pathway inhibitors by protecting the mTOR/4EBP1/Mcl-1 pathway through STAT5 activation in acute myeloid leukemia

PubMed Central

Nogami, Ayako; Oshikawa, Gaku; Okada, Keigo; Fukutake, Shusaku; Umezawa, Yoshihiro; Nagao, Toshikage; Kurosu, Tetsuya; Miura, Osamu

2015-01-01

FLT3-ITD and FLT3-TKD are the most frequent tyrosine kinase mutations in acute myeloid leukemia (AML), with the former associated with poor prognosis. Here, we show that the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 induced apoptosis through the mitochondria-mediated intrinsic pathway more efficiently in hematopoietic 32D cells driven by FLT3-TKD (32D/TKD) than FLT3-ITD (32D/ITD), which robustly activated STAT5. The resistance to GDC-0941 and MK-2206 was gained by expression of the constitutively activated STAT5 mutant STAT5A1*6 in 32D/TKD cells, while it was abrogated by the STAT5 inhibitor pimozide in 32D/ITD cells or FLT3-ITD-expressing human leukemic MV4–11 cells. GDC-0941 or MK-2206 induced dephosphorylation of 4EBP1 more conspicuously in 32D/TKD than in 32D/ITD, which was prevented or augmented by STAT5A1*6 or pimozide, respectively, and correlated with downregulation of the eIF4E/eIF4G complex formation and Mcl-1 expression. Furthermore, exogenous expression of Mcl-1 endowed resistance to GDC-0941 and MK-2206 on 32D/TKD cells. Finally, it was confirmed in primary AML cells with FLT3-ITD that pimozide enhanced 4EBP1 dephosphorylation and Mcl-1 downregulation to augment cytotoxicity of GDC-0941. These data suggest that the robust STAT5 activation by FLT3-ITD protects cells treated with the PI3K/Akt pathway inhibitors from apoptosis by maintaining Mcl-1 expression through the mTORC1/4EBP1/eIF4E pathway. PMID:25826077

FLT3-ITD confers resistance to the PI3K/Akt pathway inhibitors by protecting the mTOR/4EBP1/Mcl-1 pathway through STAT5 activation in acute myeloid leukemia.

PubMed

Nogami, Ayako; Oshikawa, Gaku; Okada, Keigo; Fukutake, Shusaku; Umezawa, Yoshihiro; Nagao, Toshikage; Kurosu, Tetsuya; Miura, Osamu

2015-04-20

FLT3-ITD and FLT3-TKD are the most frequent tyrosine kinase mutations in acute myeloid leukemia (AML), with the former associated with poor prognosis. Here, we show that the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 induced apoptosis through the mitochondria-mediated intrinsic pathway more efficiently in hematopoietic 32D cells driven by FLT3-TKD (32D/TKD) than FLT3-ITD (32D/ITD), which robustly activated STAT5. The resistance to GDC-0941 and MK-2206 was gained by expression of the constitutively activated STAT5 mutant STAT5A1*6 in 32D/TKD cells, while it was abrogated by the STAT5 inhibitor pimozide in 32D/ITD cells or FLT3-ITD-expressing human leukemic MV4-11 cells. GDC-0941 or MK-2206 induced dephosphorylation of 4EBP1 more conspicuously in 32D/TKD than in 32D/ITD, which was prevented or augmented by STAT5A1*6 or pimozide, respectively, and correlated with downregulation of the eIF4E/eIF4G complex formation and Mcl-1 expression. Furthermore, exogenous expression of Mcl-1 endowed resistance to GDC-0941 and MK-2206 on 32D/TKD cells. Finally, it was confirmed in primary AML cells with FLT3-ITD that pimozide enhanced 4EBP1 dephosphorylation and Mcl-1 downregulation to augment cytotoxicity of GDC-0941. These data suggest that the robust STAT5 activation by FLT3-ITD protects cells treated with the PI3K/Akt pathway inhibitors from apoptosis by maintaining Mcl-1 expression through the mTORC1/4EBP1/eIF4E pathway.

Development of the sound localization cues in cats

NASA Astrophysics Data System (ADS)

Tollin, Daniel J.

2004-05-01

Cats are a common model for developmental studies of the psychophysical and physiological mechanisms of sound localization. Yet, there are few studies on the development of the acoustical cues to location in cats. The magnitude of the three main cues, interaural differences in time (ITDs) and level (ILDs), and monaural spectral shape cues, vary with location in adults. However, the increasing interaural distance associated with a growing head and pinnae during development will result in cues that change continuously until maturation is complete. Here, we report measurements, in cats aged 1 week to adulthood, of the physical dimensions of the head and pinnae and the localization cues, computed from measurements of directional transfer functions. At 1 week, ILD depended little on azimuth for frequencies <6-7 kHz, maximum ITD was 175 μs, and for sources varying in elevation, a prominent spectral notch was located at higher frequencies than in the older cats. As cats develop, the spectral cues and the frequencies at which ILDs become substantial (>10 dB) shift to lower frequencies, and the maximum ITD increases to nearly 370 μs. Changes in the cues are correlated with the increasing size of the head and pinnae. [Work supported by NIDCD DC05122.

A potential therapeutic target for FLT3-ITD AML: PIM1 Kinase

PubMed Central

Fathi, Amir T.; Arowojolu, Omotayo; Swinnen, Ian; Sato, Takashi; Rajkhowa, Trivikram; Small, Donald; Marmsater, Fredrik; Robinson, John E.; Gross, Stefan David; Martinson, Matthew; Allen, Shelley; Kallan, Nicholas C.; Levis, Mark

2011-01-01

Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) mutation have a poor prognosis, and FLT3 inhibitors are now under clinical investigation. PIM1, a serine/threonine kinase, is up-regulated in FLT3-ITD AML and may be involved in FLT3-mediated leukemogenesis. We employed a PIM1 inhibitor, AR00459339 (Array Biopharma Inc.), to investigate the effect of PIM1 inhibition in FLT3-mutant AML. Like FLT3 inhibitors, AR00459339 was preferentially cytotoxic to FLT3-ITD cells, as demonstrated in the MV4-11, Molm-14, and TF/ITD cell lines, as well as 12 FLT3-ITD primary samples. Unlike FLT3 inhibitors, AR00459339 did not suppress phosphorylation of FLT3, but did promote the de-phosphorylation of downstream FLT3 targets, STAT5, AKT, and BAD. Combining AR00459339 with a FLT3 inhibitor resulted in additive to mildly synergistic cytotoxic effects. AR00459339 was cytotoxic to FLT3-ITD samples from patients with secondary resistance to FLT3 inhibitors, suggesting a novel benefit to combining these agents. We conclude that PIM1 appears to be closely associated with FLT3 signaling, and that inhibition of PIM1 may hold therapeutic promise, either as monotherapy, or by overcoming resistance to FLT3 inhibitors. PMID:21802138

Sea ice floe size distribution in the marginal ice zone: Theory and numerical experiments

NASA Astrophysics Data System (ADS)

Zhang, Jinlun; Schweiger, Axel; Steele, Michael; Stern, Harry

2015-05-01

To better describe the state of sea ice in the marginal ice zone (MIZ) with floes of varying thicknesses and sizes, both an ice thickness distribution (ITD) and a floe size distribution (FSD) are needed. In this work, we have developed a FSD theory that is coupled to the ITD theory of Thorndike et al. (1975) in order to explicitly simulate the evolution of FSD and ITD jointly. The FSD theory includes a FSD function and a FSD conservation equation in parallel with the ITD equation. The FSD equation takes into account changes in FSD due to ice advection, thermodynamic growth, and lateral melting. It also includes changes in FSD because of mechanical redistribution of floe size due to ice ridging and, particularly, ice fragmentation induced by stochastic ocean surface waves. The floe size redistribution due to ice fragmentation is based on the assumption that wave-induced breakup is a random process such that when an ice floe is broken, floes of any smaller sizes have an equal opportunity to form, without being either favored or excluded. To focus only on the properties of mechanical floe size redistribution, the FSD theory is implemented in a simplified ITD and FSD sea ice model for idealized numerical experiments. Model results show that the simulated cumulative floe number distribution (CFND) follows a power law as observed by satellites and airborne surveys. The simulated values of the exponent of the power law, with varying levels of ice breakups, are also in the range of the observations. It is found that floe size redistribution and the resulting FSD and mean floe size do not depend on how floe size categories are partitioned over a given floe size range. The ability to explicitly simulate multicategory FSD and ITD together may help to incorporate additional model physics, such as FSD-dependent ice mechanics, surface exchange of heat, mass, and momentum, and wave-ice interactions.

Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy.

PubMed

Boissel, N; Cayuela, J M; Preudhomme, C; Thomas, X; Grardel, N; Fund, X; Tigaud, I; Raffoux, E; Rousselot, P; Sigaux, F; Degos, L; Castaigne, S; Fenaux, P; Dombret, H

2002-09-01

FLT3 internal tandem duplications (FLT3-ITDs) are present in nearly 25% of patients with AML and have been associated with poor response to conventional therapy and poor outcome. We retrospectively evaluated the effect of reinforced courses of chemotherapy on the prognostic value of FLT3-ITDs in 159 AML patients prospectively enrolled in the ALFA-9000 trial, which randomly compared three reinforced induction regimens (standard 3+7 including high-dose daunorubicin, double induction, and timed-sequential therapy). FLT3-ITD was present in 40/159 (25%) blast samples and associated with high WBC (P = 0.002) and cytogenetics (P < 0.001) with a higher incidence (35%) in patients with a normal karyotype. There was no difference in CR rate between FLT3-wt and FLT3-ITD patients (80% vs 78%). Relapse-free survival (RFS) was similar in both groups (5-year RFS, 33% vs 32%; P = 0.41), even after adjustment for age, sex, WBC, cytogenetics, and treatment arm. A trend to a worse survival was observed in the FLT3-ITD group (estimated 5-year OS, 23% vs 37%; P = 0.09), mainly in patients with a normal karyotype. This was associated with a dramatic outcome in relapsing FLT3-ITD patients (estimated 3-year post-relapse survival, 0% vs 27%; P = 0.04). These results suggest that the bad prognosis associated with FLT3-ITDs in AML might be partly overcome using reinforced chemotherapy. Early detection of FLT3 mutations might thus be useful to intensify induction as well as post-remission therapy in FLT3-ITD patients.

Breakdown of the FLT3-ITD/STAT5 axis and synergistic apoptosis induction by the histone deacetylase inhibitor panobinostat and FLT3-specific inhibitors.

PubMed

Pietschmann, Kristin; Bolck, Hella Anna; Buchwald, Marc; Spielberg, Steffi; Polzer, Harald; Spiekermann, Karsten; Bug, Gesine; Heinzel, Thorsten; Böhmer, Frank-Dietmar; Krämer, Oliver H

2012-11-01

Activating mutations of the class III receptor tyrosine kinase FLT3 are the most frequent molecular aberration in acute myeloid leukemia (AML). Mutant FLT3 accelerates proliferation, suppresses apoptosis, and correlates with poor prognosis. Therefore, it is a promising therapeutic target. Here, we show that RNA interference against FLT3 with an internal tandem duplication (FLT3-ITD) potentiates the efficacy of the histone deacetylase inhibitor (HDACi) panobinostat (LBH589) against AML cells expressing FLT3-ITD. Similar to RNA interference, tyrosine kinase inhibitors (TKI; AC220/cpd.102/PKC412) in combination with LBH589 exhibit superior activity against AML cells. Median dose-effect analyses of drug-induced apoptosis rates of AML cells (MV4-11 and MOLM-13) revealed combination index (CI) values indicating strong synergism. AC220, the most potent and FLT3-specific TKI, shows highest synergism with LBH589 in the low nanomolar range. A 4-hour exposure to LBH589 + AC220 already generates more than 50% apoptosis after 24 hours. Different cell lines lacking FLT3-ITD as well as normal peripheral blood mononuclear cells are not significantly affected by LBH589 + TKI, showing the specificity of this treatment regimen. Immunoblot analyses show that LBH589 + TKI induce apoptosis via degradation of FLT3-ITD and its prosurvival target STAT5. Previously, we showed the LBH589-induced proteasomal degradation of FLT3-ITD. Here, we show that activated caspase-3 also contributes to the degradation of FLT3-ITD and that STAT5 is a direct target of this protease. Our data strongly emphasize HDACi/TKI drug combinations as promising modality for the treatment of FLT3-ITD-positive AMLs. ©2012 AACR.

A trial of an impedance threshold device in out-of-hospital cardiac arrest.

PubMed

Aufderheide, Tom P; Nichol, Graham; Rea, Thomas D; Brown, Siobhan P; Leroux, Brian G; Pepe, Paul E; Kudenchuk, Peter J; Christenson, Jim; Daya, Mohamud R; Dorian, Paul; Callaway, Clifton W; Idris, Ahamed H; Andrusiek, Douglas; Stephens, Shannon W; Hostler, David; Davis, Daniel P; Dunford, James V; Pirrallo, Ronald G; Stiell, Ian G; Clement, Catherine M; Craig, Alan; Van Ottingham, Lois; Schmidt, Terri A; Wang, Henry E; Weisfeldt, Myron L; Ornato, Joseph P; Sopko, George

2011-09-01

The impedance threshold device (ITD) is designed to enhance venous return and cardiac output during cardiopulmonary resuscitation (CPR) by increasing the degree of negative intrathoracic pressure. Previous studies have suggested that the use of an ITD during CPR may improve survival rates after cardiac arrest. We compared the use of an active ITD with that of a sham ITD in patients with out-of-hospital cardiac arrest who underwent standard CPR at 10 sites in the United States and Canada. Patients, investigators, study coordinators, and all care providers were unaware of the treatment assignments. The primary outcome was survival to hospital discharge with satisfactory function (i.e., a score of ≤3 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating greater disability). Of 8718 patients included in the analysis, 4345 were randomly assigned to treatment with a sham ITD and 4373 to treatment with an active device. A total of 260 patients (6.0%) in the sham-ITD group and 254 patients (5.8%) in the active-ITD group met the primary outcome (risk difference adjusted for sequential monitoring, -0.1 percentage points; 95% confidence interval, -1.1 to 0.8; P=0.71). There were also no significant differences in the secondary outcomes, including rates of return of spontaneous circulation on arrival at the emergency department, survival to hospital admission, and survival to hospital discharge. Use of the ITD did not significantly improve survival with satisfactory function among patients with out-of-hospital cardiac arrest receiving standard CPR. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706.).

Resuscitation Outcomes Consortium (ROC) PRIMED cardiac arrest trial methods part 1: rationale and methodology for the impedance threshold device (ITD) protocol.

PubMed

Aufderheide, Tom P; Kudenchuk, Peter J; Hedges, Jerris R; Nichol, Graham; Kerber, Richard E; Dorian, Paul; Davis, Daniel P; Idris, Ahamed H; Callaway, Clifton W; Emerson, Scott; Stiell, Ian G; Terndrup, Thomas E

2008-08-01

The primary aim of this study is to compare survival to hospital discharge with a modified Rankin score (MRS)< or =3 between standard cardiopulmonary resuscitation (CPR) plus an active impedance threshold device (ITD) versus standard CPR plus a sham ITD in patients with out-of-hospital cardiac arrest. Secondary aims are to compare functional status and depression at discharge and at 3 and 6 months post-discharge in survivors. Prospective, double-blind, randomized, controlled, clinical trial. Patients with non-traumatic out-of-hospital cardiac arrest treated by emergency medical services (EMS) providers. EMS systems participating in the Resuscitation Outcomes Consortium. Based on a one-sided significance level of 0.025, power=0.90, a survival with MRS< or =3 to discharge rate of 5.33% with standard CPR and sham ITD, and two interim analyses, a maximum of 14,742 evaluable patients are needed to detect a 6.69% survival with MRS< or =3 to discharge with standard CPR and active ITD (1.36% absolute survival difference). If the ITD demonstrates the hypothesized improvement in survival, it is estimated that 2700 deaths from cardiac arrest per year would be averted in North America alone.

Why Internally Coupled Ears (ICE) Work Well

NASA Astrophysics Data System (ADS)

van Hemmen, J. Leo

2014-03-01

Many vertebrates, such as frogs and lizards, have an air-filled cavity between left and right eardrum, i.e., internally coupled ears (ICE). Depending on source direction, internal time (iTD) and level (iLD) difference as experienced by the animal's auditory system may greatly exceed [C. Vossen et al., JASA 128 (2010) 909-918] the external, or interaural, time and level difference (ITD and ILD). Sensory processing only encodes iTD and iLD. We present an extension of ICE theory so as to elucidate the underlying physics. First, the membrane properties of the eardrum explain why for low frequencies iTD dominates whereas iLD does so for higher frequencies. Second, the plateau of iTD = γ ITD for constant 1 < γ < 5 and variable input frequency <ν∘ follows; e.g., for the Tockay gecko ν∘ ~ 1 . 5 kHz. Third, we use a sectorial instead of circular membrane to quantify the effect of the extracolumella embedded in the tympanum and connecting with the cochlea. The main parameters can be adjusted so that the model is species independent. Work done in collaboration with A.P. Vedurmudi and J. Goulet; partially supported by BCCN-Munich.

Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside.

PubMed

Shabbir, Munira; Stuart, Robert

2010-03-01

Internal tandem duplication of the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common recurring mutation in acute myeloid leukemia (AML) with normal karyotype, and the presence of FLT3-ITD confers a poor prognosis on this large subgroup of AML patients. Since the discovery of lestaurtinib as a potent FLT3 inhibitor, in 1985, there has been considerable interest in the development of this agent (CEP-701, Cephalon, Frazer, PA, USA) for treatment of this population. An extensive literature search was conducted that included published articles and abstracts on the preclinical and clinical development of this agent spanning the last decade. The review describes the historical development of this agent and reviews the available preclinical and clinical data on lestaurtinib and expands on potential future directions in development of this agent. Lestaurtinib is a multi targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.

The Relative Contribution of Interaural Time and Magnitude Cues to Dynamic Sound Localization

NASA Technical Reports Server (NTRS)

Wenzel, Elizabeth M.; Null, Cynthia H. (Technical Monitor)

1995-01-01

This paper presents preliminary data from a study examining the relative contribution of interaural time differences (ITDs) and interaural level differences (ILDs) to the localization of virtual sound sources both with and without head motion. The listeners' task was to estimate the apparent direction and distance of virtual sources (broadband noise) presented over headphones. Stimuli were synthesized from minimum phase representations of nonindividualized directional transfer functions; binaural magnitude spectra were derived from the minimum phase estimates and ITDs were represented as a pure delay. During dynamic conditions, listeners were encouraged to move their heads; the position of the listener's head was tracked and the stimuli were synthesized in real time using a Convolvotron to simulate a stationary external sound source. ILDs and ITDs were either correctly or incorrectly correlated with head motion: (1) both ILDs and ITDs correctly correlated, (2) ILDs correct, ITD fixed at 0 deg azimuth and 0 deg elevation, (3) ITDs correct, ILDs fixed at 0 deg, 0 deg. Similar conditions were run for static conditions except that none of the cues changed with head motion. The data indicated that, compared to static conditions, head movements helped listeners to resolve confusions primarily when ILDs were correctly correlated, although a smaller effect was also seen for correct ITDs. Together with the results for static conditions, the data suggest that localization tends to be dominated by the cue that is most reliable or consistent, when reliability is defined by consistency over time as well as across frequency bands.

A circuit for detection of interaural time differences in the nucleus laminaris of turtles.

PubMed

Willis, Katie L; Carr, Catherine E

2017-11-15

The physiological hearing range of turtles is approximately 50-1000 Hz, as determined by cochlear microphonics ( Wever and Vernon, 1956a). These low frequencies can constrain sound localization, particularly in red-eared slider turtles, which are freshwater turtles with small heads and isolated middle ears. To determine if these turtles were sensitive to interaural time differences (ITDs), we investigated the connections and physiology of their auditory brainstem nuclei. Tract tracing experiments showed that cranial nerve VIII bifurcated to terminate in the first-order nucleus magnocellularis (NM) and nucleus angularis (NA), and the NM projected bilaterally to the nucleus laminaris (NL). As the NL received inputs from each side, we developed an isolated head preparation to examine responses to binaural auditory stimulation. Magnocellularis and laminaris units responded to frequencies from 100 to 600 Hz, and phase-locked reliably to the auditory stimulus. Responses from the NL were binaural, and sensitive to ITD. Measures of characteristic delay revealed best ITDs around ±200 μs, and NL neurons typically had characteristic phases close to 0, consistent with binaural excitation. Thus, turtles encode ITDs within their physiological range, and their auditory brainstem nuclei have similar connections and cell types to other reptiles. © 2017. Published by The Company of Biologists Ltd.

FLT3-regulated antigens as targets for leukemia-reactive cytotoxic T lymphocytes

PubMed Central

Brackertz, B; Conrad, H; Daniel, J; Kast, B; Krönig, H; Busch, D H; Adamski, J; Peschel, C; Bernhard, H

2011-01-01

The FMS-like tyrosine kinase 3 (FLT3) is highly expressed in acute myeloid leukemia (AML). Internal tandem duplications (ITD) of the juxtamembrane domain lead to the constitutive activation of the FLT3 kinase inducing the activation of multiple genes, which may result in the expression of leukemia-associated antigens (LAAs). We analyzed the regulation of LAA in FLT3-wild-type (WT)- and FLT3-ITD+ myeloid cells to identify potential targets for antigen-specific immunotherapy for AML patients. Antigens, such as PR-3, RHAMM, Survivin, WT-1 and PRAME, were upregulated by constitutively active FLT3-ITD as well as FLT3-WT activated by FLT3 ligand (FL). Cytotoxic T-cell (CTL) clones against PR-3, RHAMM, Survivin and an AML-directed CTL clone recognized AML cell lines and primary AML blasts expressing FLT3-ITD, as well as FLT3-WT+ myeloid dendritic cells in the presence of FL. Downregulation of FLT3 led to the abolishment of CTL recognition. Comparing our findings concerning LAA upregulation by the FLT3 kinase with those already made for the Bcr-Abl kinase, we found analogies in the LAA expression pattern. Antigens upregulated by both FLT3 and Bcr-Abl may be promising targets for the development of immunotherapeutical approaches against myeloid leukemia of different origin. PMID:22829124

Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation.

PubMed

Kapoor, Shivani; Natarajan, Karthika; Baldwin, Patrick R; Doshi, Kshama A; Lapidus, Rena G; Mathias, Trevor J; Scarpa, Mario; Trotta, Rossana; Davila, Eduardo; Kraus, Manfred; Huszar, Dennis; Tron, Adriana E; Perrotti, Danilo; Baer, Maria R

2018-01-01

Purpose: fms -like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G 1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234-47. ©2017 AACR . ©2017 American Association for Cancer Research.

Evaluation of an Impedance Threshold Device as a VIIP Countermeasure

NASA Technical Reports Server (NTRS)

Ebert, D.; Macias, B.; Garcia, K.; Stenger, M.; Hargens, A.; Johnston, S.

2016-01-01

Visual Impairment /Intracranial Pressure (VIIP) is a top human spaceflight risk for which NASA does not currently have a proven mitigation strategy. Thigh cuffs (Braslets) and lower body negative pressure (LBNP; Chibis) devices have been or are currently being evaluated as a means to reduce VIIP signs and symptoms, but these methods alone may not provide sufficient relief of cephalic venous congestion and VIIP symptoms. Additionally, current LBNP devices are too large and cumbersome for their systematic use as a countermeasure. Therefore, a novel approach is needed that is easy to implement and provides specific relief of symptoms. This investigation will evaluate an impedance threshold device (ITD) as a VIIP countermeasure. The ITD works by providing up to 7 cm H2O (approximately 5 mmHg) resistance to inspiratory air flow, effectively turning the thorax into a vacuum pump upon each inhalation which lowers the intrathoracic pressure (ITP) and facilitates venous return to the heart. The ITD is FDA-approved and was developed to augment venous return to the central circulation and increase cardiac output during cardiopulmonary resuscitation (CPR) and in patients with hypotension. While the effect of ITD on CPR survival outcomes is controversial, the ITD's ability to lower ITP with a concomitant decrease in intracranial pressure (ICP) is well documented. A similar concept that creates negative ITP during exhalation (intrathoracic pressure regulator; ITPR) decreased ICP in 16 of 20 patients with elevated ICP in a hospital pilot study. ITP and central venous pressure (CVP) have been shown to decrease in microgravity however ITP drops more than CVP, indicating an increased transmural CVP. This could explain the paradoxical distention of jugular veins (JV) in microgravity despite lower absolute CVP and also suggests that JV transmural pressure is not dramatically elevated. Use of an ITD may lower JV pressure enough to remove or relieve cephalic venous congestion. During spaceflight experiments with Braslet thigh cuffs and modified (open-glottis) Mueller maneuvers, Braslets alone reduced cardiac preload but only reduced the internal JV (IJV) cross sectional area by 23%. The addition of Mueller maneuvers resulted in an IJV area reduction of 48%. This project will test if ITD essentially applies a Mueller maneuver with added negative ITP in every respiratory cycle, acting to: 1) reduce venous congestion in the neck and 2) potentially lower ICP. The expected mechanism of action is that in microgravity (or an analog) blood is relocated toward the heart from vasculature in the head and neck. Once validated, the ITD would be an exceptionally easy countermeasure to deploy and test on the ISS. Dosage could be altered though 1) duration of application and 2) inspiratory resistance set point. Effects could be additionally enhanced through co-application with other countermeasures such as thigh cuffs or LBNP.

Evaluation of an Impedance Threshold Device as a VIIP Countermeasure

NASA Technical Reports Server (NTRS)

Ebert, Douglas; Macias, Brandon; Sargsyan, Ashot; Garcia, Kathleen; Stenger, Michael; Hargens, Alan; Johnston, Smith; Kemp, David; Danielson, Richard

2016-01-01

Visual Impairment/Intracranial Pressure (VIIP) is a top human spaceflight risk for which NASA does not currently have a proven mitigation strategy. Thigh cuffs (Braslets) and lower body negative pressure (LBNP; Chibis) devices have been or are currently being evaluated as a means to reduce VIIP signs and symptoms, but these methods alone may not provide sufficient relief of cephalic venous congestion and VIIP symptoms. Additionally, current LBNP devices are too large and cumbersome for their systematic use as a countermeasure. Therefore, a novel approach is needed that is easy to implement and provides specific relief of symptoms. This investigation will evaluate an impedance threshold device (ITD) as a VIIP countermeasure. The ITD works by providing up to 7 cm H2O (approximately 5 mmHg) resistance to inspiratory air flow, effectively turning the thorax into a vacuum pump upon each inhalation which lowers the intrathoracic pressure (ITP) and facilitates venous return to the heart. The ITD is FDA-approved and was developed to augment venous return to the central circulation and increase cardiac output during cardiopulmonary resuscitation (CPR) and in patients with hypotension. While the effect of ITD on CPR survival outcomes is controversial, the ITD's ability to lower ITP with a concomitant decrease in intracranial pressure (ICP) is well documented. A similar concept that creates negative ITP during exhalation (intrathoracic pressure regulator; ITPR) decreased ICP in 16 of 20 patients with elevated ICP in a hospital pilot study. ITP and central venous pressure (CVP) have been shown to decrease in microgravity however ITP drops more than CVP, indicating an increased transmural CVP. This could explain the paradoxical distention of jugular veins (JV) in microgravity despite lower absolute CVP and also suggests that JV transmural pressure is not dramatically elevated. Use of an ITD may lower JV pressure enough to remove or relieve cephalic venous congestion. During spaceflight experiments with Braslet thigh cuffs and modified (open-glottis) Mueller maneuvers, Braslets alone reduced cardiac preload but only reduced the internal JV (IJV) cross sectional area by 23%. The addition of Mueller maneuvers resulted in an IJV area reduction of 48%. This project will test if ITD essentially applies a Mueller maneuver with added negative ITP in every respiratory cycle, acting to: 1) reduce venous congestion in the neck and 2) potentially lower ICP. The expected mechanism of action is that in microgravity (or an analog) blood is relocated toward the heart from vasculature in the head and neck. Once validated, the ITD would be an exceptionally easy countermeasure to deploy and test on the ISS. Dosage could be altered though 1) duration of application and 2) inspiratory resistance set point. Effects could be additionally enhanced through co-application with other countermeasures such as thigh cuffs or LBNP.

The relative immunity of high-frequency transposed stimuli to low-frequency binaural interference

NASA Astrophysics Data System (ADS)

Bernstein, Leslie R.; Trahiotis, Constantine

2004-05-01

We have recently demonstrated that high-frequency transposed stimuli, having envelopes designed to provide high-frequency channels with information similar to that normally available in only low-frequency channels, yield threshold-ITDs and extents of laterality comparable to those obtained with conventional low-frequency stimuli. This enhanced potency of ITDs conveyed by high-frequency transposed stimuli, as compared to conventional high-frequency stimuli, suggested to us that ITDs conveyed by transposed stimuli might be relatively immune to the presence of low-frequency binaural interferers. To investigate this issue, threshold-ITDs and extents of laterality were measured with a variety of conventional and transposed targets centered at 4 kHz. The targets were presented either in the presence or absence of a simultaneously gated diotic noise centered at 500 Hz, the interferer. As expected, the presence of the low-frequency interferer resulted in substantially elevated threshold-ITDs and reduced extents of laterality for the conventional high-frequency stimuli. In contrast, these interference effects were either greatly attenuated or absent for ITDs conveyed by the high-frequency transposed targets. The results will be discussed in the context of current models of binaural interference. [Work supported by NIH DC 04147, NIH DC04073, NIH DC 002304.

Dystonia gene in Ashkenazi Jewish population is located on chromosome 9q32-34.

PubMed

Kramer, P L; de Leon, D; Ozelius, L; Risch, N; Bressman, S B; Brin, M F; Schuback, D E; Burke, R E; Kwiatkowski, D J; Shale, H

1990-02-01

Idiopathic torsion dystonia (ITD) is a neurological disorder characterized by sustained muscle contractions that appear as twisting movements of the limbs, trunk, and/or neck, which can progress to abnormal postures. Most familial forms of ITD follow autosomal dominant transmission with reduced penetrance. The frequency of ITD in the Ashkenazi Jewish population is five to ten times greater than that in other groups. Recently, a gene for ITD (DYT1) in a non-Jewish kindred was located on chromosome 9q32-34, with tight linkage to the gene encoding gelsolin (GSN). In the present study linkage analysis using DNA polymorphisms is used to locate a gene responsible for susceptibility to ITD in 12 Ashkenazi Jewish families. This dystonia gene exhibits close linkage with the gene encoding argininosuccinate synthetase (ASS), and appears by multipoint analysis to lie in the q32-34 region of chromosome 9, a region that also contains the loci for gelsolin and dopamine-beta-hydroxylase. The same gene may be responsible for ITD both in the non-Jewish kindred mentioned above and in the Ashkenazi Jewish families presented here. However, because there is substantial difference between the penetrance of the dominant allele in these two groups, two different mutations may be operating to produce susceptibility to this disease in the two groups.

Resuscitation Outcomes Consortium (ROC) PRIMED Cardiac Arrest Trial Methods, Part 1: Rationale and Methodology for the Impedance Threshold Device (ITD) Protocol

PubMed Central

Aufderheide, Tom P.; Kudenchuk, Peter J.; Hedges, Jerris R.; Nichol, Graham; Kerber, Richard E.; Dorian, Paul; Davis, Daniel P.; Idris, Ahamed H.; Callaway, Clifton W.; Emerson, Scott; Stiell, Ian G.; Terndrup, Thomas E.

2013-01-01

Aim The primary aim of this study is to compare survival to hospital discharge with a modified Rankin score (MRS) ≤3 between standard cardiopulmonary resuscitation (CPR) plus an active impedance threshold device (ITD) versus standard CPR plus a sham ITD in patients with out-of-hospital cardiac arrest. Secondary aims are to compare functional status and depression at discharge and at 3 and 6 months post discharge in survivors. Materials and Methods Design Prospective, double-blind, randomized, controlled, clinical trial. Population Patients with non-traumatic out-of-hospital cardiac arrest treated by emergency medical services (EMS) providers. Setting EMS systems participating in the Resuscitation Outcomes Consortium. Sample Size Based on a one-sided significance level of 0.025, power = 0.90, a survival with MRS ≤ 3 to discharge rate of 5.33% with standard CPR and sham ITD, and two interim analyses, a maximum of 14,742 evaluable patients are needed to detect a 6.69% survival with MRS ≤ 3 to discharge with standard CPR and active ITD (1.36% absolute survival difference). Conclusion If the ITD demonstrates the hypothesized improvement in survival, it is estimated that2,700 deaths from cardiac arrest per year would be averted in North America alone. PMID:18487005

Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia

PubMed Central

Park, Jung Eun; Yuen, Hiu Fung; Zhou, Jian Biao; Al-aidaroos, Abdul Qader O; Guo, Ke; Valk, Peter J; Zhang, Shu Dong; Chng, Wee Joo; Hong, Cheng William; Mills, Ken; Zeng, Qi

2013-01-01

FLT3-ITD mutations are prevalent mutations in acute myeloid leukaemia (AML). PRL-3, a metastasis-associated phosphatase, is a downstream target of FLT3-ITD. This study investigates the regulation and function of PRL-3 in leukaemia cell lines and AML patients associated with FLT3-ITD mutations. PRL-3 expression is upregulated by the FLT3-STAT5 signalling pathway in leukaemia cells, leading an activation of AP-1 transcription factors via ERK and JNK pathways. PRL-3-depleted AML cells showed a significant decrease in cell growth. Clinically, high PRL-3 mRNA expression was associated with FLT3-ITD mutations in four independent AML datasets with 1158 patients. Multivariable Cox-regression analysis on our Cohort 1 with 221 patients identified PRL-3 as a novel prognostic marker independent of other clinical parameters. Kaplan–Meier analysis showed high PRL-3 mRNA expression was significantly associated with poorer survival among 491 patients with normal karyotype. Targeting PRL-3 reversed the oncogenic effects in FLT3-ITD AML models in vitro and in vivo. Herein, we suggest that PRL-3 could serve as a prognostic marker to predict poorer survival and as a promising novel therapeutic target for AML patients. PMID:23929599

Sensitivity to Envelope Interaural Time Differences at High Modulation Rates

PubMed Central

Bleeck, Stefan; McAlpine, David

2015-01-01

Sensitivity to interaural time differences (ITDs) conveyed in the temporal fine structure of low-frequency tones and the modulated envelopes of high-frequency sounds are considered comparable, particularly for envelopes shaped to transmit similar fidelity of temporal information normally present for low-frequency sounds. Nevertheless, discrimination performance for envelope modulation rates above a few hundred Hertz is reported to be poor—to the point of discrimination thresholds being unattainable—compared with the much higher (>1,000 Hz) limit for low-frequency ITD sensitivity, suggesting the presence of a low-pass filter in the envelope domain. Further, performance for identical modulation rates appears to decline with increasing carrier frequency, supporting the view that the low-pass characteristics observed for envelope ITD processing is carrier-frequency dependent. Here, we assessed listeners’ sensitivity to ITDs conveyed in pure tones and in the modulated envelopes of high-frequency tones. ITD discrimination for the modulated high-frequency tones was measured as a function of both modulation rate and carrier frequency. Some well-trained listeners appear able to discriminate ITDs extremely well, even at modulation rates well beyond 500 Hz, for 4-kHz carriers. For one listener, thresholds were even obtained for a modulation rate of 800 Hz. The highest modulation rate for which thresholds could be obtained declined with increasing carrier frequency for all listeners. At 10 kHz, the highest modulation rate at which thresholds could be obtained was 600 Hz. The upper limit of sensitivity to ITDs conveyed in the envelope of high-frequency modulated sounds appears to be higher than previously considered. PMID:26721926

Reduced temporal processing in older, normal-hearing listeners evident from electrophysiological responses to shifts in interaural time difference.

PubMed

Ozmeral, Erol J; Eddins, David A; Eddins, Ann C

2016-12-01

Previous electrophysiological studies of interaural time difference (ITD) processing have demonstrated that ITDs are represented by a nontopographic population rate code. Rather than narrow tuning to ITDs, neural channels have broad tuning to ITDs in either the left or right auditory hemifield, and the relative activity between the channels determines the perceived lateralization of the sound. With advancing age, spatial perception weakens and poor temporal processing contributes to declining spatial acuity. At present, it is unclear whether age-related temporal processing deficits are due to poor inhibitory controls in the auditory system or degraded neural synchrony at the periphery. Cortical processing of spatial cues based on a hemifield code are susceptible to potential age-related physiological changes. We consider two distinct predictions of age-related changes to ITD sensitivity: declines in inhibitory mechanisms would lead to increased excitation and medial shifts to rate-azimuth functions, whereas a general reduction in neural synchrony would lead to reduced excitation and shallower slopes in the rate-azimuth function. The current study tested these possibilities by measuring an evoked response to ITD shifts in a narrow-band noise. Results were more in line with the latter outcome, both from measured latencies and amplitudes of the global field potentials and source-localized waveforms in the left and right auditory cortices. The measured responses for older listeners also tended to have reduced asymmetric distribution of activity in response to ITD shifts, which is consistent with other sensory and cognitive processing models of aging. Copyright © 2016 the American Physiological Society.

Acidosis mediates recurrent hypoglycemia-induced increase in ischemic brain injury in treated diabetic rats.

PubMed

Rehni, Ashish K; Shukla, Vibha; Perez-Pinzon, Miguel A; Dave, Kunjan R

2018-03-15

Cerebral ischemia is a serious possible manifestation of diabetic vascular disease. Recurrent hypoglycemia (RH) enhances ischemic brain injury in insulin-treated diabetic (ITD) rats. In the present study, we determined the role of ischemic acidosis in enhanced ischemic brain damage in RH-exposed ITD rats. Diabetic rats were treated with insulin and mild/moderate RH was induced for 5 days. Three sets of experiments were performed. The first set evaluated the effects of RH exposure on global cerebral ischemia-induced acidosis in ITD rats. The second set evaluated the effect of an alkalizing agent (Tris-(hydroxymethyl)-aminomethane: THAM) on ischemic acidosis-induced brain injury in RH-exposed ITD rats. The third experiment evaluated the effect of the glucose transporter (GLUT) inhibitor on ischemic acidosis-induced brain injury in RH-exposed ITD rats. Hippocampal pH and lactate were measured during ischemia and early reperfusion for all three experiments. Neuronal survival in Cornu Ammonis 1 (CA1) hippocampus served as a measure of ischemic brain injury. Prior RH exposure increases lactate concentration and decreases pH during ischemia and early reperfusion when compared to controls. THAM and GLUT inhibitor treatments attenuated RH-induced increase in ischemic acidosis. GLUT inhibitor treatment reduced the RH-induced increase in lactate levels. Both THAM and GLUT inhibitor treatments significantly decreased ischemic damage in RH-exposed ITD rats. Ischemia causes increased acidosis in RH-exposed ITD rats via a GLUT-sensitive mechanism. Exploring downstream pathways may help understand mechanisms by which prior exposure to RH increases cerebral ischemic damage. Copyright © 2018 Elsevier Ltd. All rights reserved.

Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD.

PubMed

Kazi, Julhash U; Chougule, Rohit A; Li, Tianfeng; Su, Xianwei; Moharram, Sausan A; Rupar, Kaja; Marhäll, Alissa; Gazi, Mohiuddin; Sun, Jianmin; Zhao, Hui; Rönnstrand, Lars

2017-07-01

The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.

Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia

PubMed Central

Dovey, Oliver M.; Cooper, Jonathan L.; Mupo, Annalisa; Grove, Carolyn S.; Lynn, Claire; Conte, Nathalie; Andrews, Robert M.; Pacharne, Suruchi; Tzelepis, Konstantinos; Vijayabaskar, M. S.; Green, Paul; Rad, Roland; Arends, Mark; Wright, Penny; Yusa, Kosuke; Bradley, Allan; Varela, Ignacio

2017-01-01

NPM1 mutations define the commonest subgroup of acute myeloid leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonly, NRAS or KRAS mutations. Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NPM1-RAS combinations. To understand the molecular basis of these observations, we compare the effects of the 2 combinations on hematopoiesis and leukemogenesis in knock-in mice. Early effects of these mutations on hematopoiesis show that compound Npm1cA/+;NrasG12D/+ or Npm1cA;Flt3ITD share a number of features: Hox gene overexpression, enhanced self-renewal, expansion of hematopoietic progenitors, and myeloid differentiation bias. However, Npm1cA;Flt3ITD mutants displayed significantly higher peripheral leukocyte counts, early depletion of common lymphoid progenitors, and a monocytic bias in comparison with the granulocytic bias in Npm1cA/+;NrasG12D/+ mutants. Underlying this was a striking molecular synergy manifested as a dramatically altered gene expression profile in Npm1cA;Flt3ITD, but not Npm1cA/+;NrasG12D/+, progenitors compared with wild-type. Both double-mutant models developed high-penetrance AML, although latency was significantly longer with Npm1cA/+;NrasG12D/+. During AML evolution, both models acquired additional copies of the mutant Flt3 or Nras alleles, but only Npm1cA/+;NrasG12D/+ mice showed acquisition of other human AML mutations, including IDH1 R132Q. We also find, using primary Cas9-expressing AMLs, that Hoxa genes and selected interactors or downstream targets are required for survival of both types of double-mutant AML. Our results show that molecular complementarity underlies the higher frequency and significantly worse prognosis associated with NPM1c/FLT3-ITD vs NPM1/NRAS-G12D-mutant AML and functionally confirm the role of HOXA genes in NPM1c-driven AML. PMID:28835438

All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo.

PubMed

Ma, Hayley S; Greenblatt, Sarah M; Shirley, Courtney M; Duffield, Amy S; Bruner, J Kyle; Li, Li; Nguyen, Bao; Jung, Eric; Aplan, Peter D; Ghiaur, Gabriel; Jones, Richard J; Small, Donald

2016-06-09

FMS-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia (AML) portends a poor prognosis, and ineffective targeting of the leukemic stem cell (LSC) population remains one of several obstacles in treating this disease. All-trans retinoic acid (ATRA) has been used in several clinical trials for the treatment of nonpromyelocytic AML with limited clinical activity observed. FLT3 tyrosine kinase inhibitors (TKIs) used as monotherapy also achieve limited clinical responses and are thus far unable to affect cure rates in AML patients. We explored the efficacy of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication (ITD)(+) LSCs. Our studies reveal highly synergistic drug activity, preferentially inducing apoptosis in FLT3/ITD(+) cell lines and patient samples. Colony-forming unit assays further demonstrate decreased clonogenicity of FLT3/ITD(+) cells upon treatment with ATRA and TKI. Most importantly, the drug combination depletes FLT3/ITD(+) LSCs in a genetic mouse model of AML, and prolongs survival of leukemic mice. Furthermore, engraftment of primary FLT3/ITD(+) patient samples is reduced in mice following treatment with FLT3 TKI and ATRA in combination, with evidence of cellular differentiation occurring in vivo. Mechanistically, we provide evidence that the synergism of ATRA and FLT3 TKIs is at least in part due to the observation that FLT3 TKI treatment upregulates the antiapoptotic protein Bcl6, limiting the drug's apoptotic effect. However, cotreatment with ATRA reduces Bcl6 expression to baseline levels through suppression of interleukin-6 receptor signaling. These studies provide evidence of the potential of this drug combination to eliminate FLT3/ITD(+) LSCs and reduce the rate of relapse in AML patients with FLT3 mutations.

Adaptation in sound localization processing induced by interaural time difference in amplitude envelope at high frequencies.

PubMed

Kawashima, Takayuki; Sato, Takao

2012-01-01

When a second sound follows a long first sound, its location appears to be perceived away from the first one (the localization/lateralization aftereffect). This aftereffect has often been considered to reflect an efficient neural coding of sound locations in the auditory system. To understand determinants of the localization aftereffect, the current study examined whether it is induced by an interaural temporal difference (ITD) in the amplitude envelope of high frequency transposed tones (over 2 kHz), which is known to function as a sound localization cue. In Experiment 1, participants were required to adjust the position of a pointer to the perceived location of test stimuli before and after adaptation. Test and adapter stimuli were amplitude modulated (AM) sounds presented at high frequencies and their positional differences were manipulated solely by the envelope ITD. Results showed that the adapter's ITD systematically affected the perceived position of test sounds to the directions expected from the localization/lateralization aftereffect when the adapter was presented at ±600 µs ITD; a corresponding significant effect was not observed for a 0 µs ITD adapter. In Experiment 2, the observed adapter effect was confirmed using a forced-choice task. It was also found that adaptation to the AM sounds at high frequencies did not significantly change the perceived position of pure-tone test stimuli in the low frequency region (128 and 256 Hz). The findings in the current study indicate that ITD in the envelope at high frequencies induces the localization aftereffect. This suggests that ITD in the high frequency region is involved in adaptive plasticity of auditory localization processing.

Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia.

PubMed

Pillinger, Genevra; Abdul-Aziz, Amina; Zaitseva, Lyubov; Lawes, Matthew; MacEwan, David J; Bowles, Kristian M; Rushworth, Stuart A

2015-08-21

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML.

Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation.

PubMed

Metzelder, S K; Schroeder, T; Lübbert, M; Ditschkowski, M; Götze, K; Scholl, S; Meyer, R G; Dreger, P; Basara, N; Fey, M F; Salih, H R; Finck, A; Pabst, T; Giagounidis, A; Kobbe, G; Wollmer, E; Finke, J; Neubauer, A; Burchert, A

2017-11-01

Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD-positive AML relapsing after allo-SCT. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chidamide in FLT3-ITD positive acute myeloid leukemia and the synergistic effect in combination with cytarabine.

PubMed

Li, Xia; Yan, Xiao; Guo, Wenjian; Huang, Xin; Huang, Jiansong; Yu, Mengxia; Ma, Zhixin; Xu, Yu; Huang, ShuJuan; Li, Chenying; Zhou, Yile; Jin, Jie

2017-06-01

Chidamide, a novel histone deacetylase inhibitor (HDACi), has been approved for treatment of T-cell lymphomas in multiple clinical trials. It has been demonstrated that chidamide can inhibit cell cycle, promote apoptosis and induce differentiation in leukemia cells, whereas its effect on acute myeloid leukemia (AML) patients with FLT3-ITD mutation has not been clarified. In this study, we found that chidamide specifically induced G0/G1 arrest and apoptosis in FLT3-ITD positive AML cells in a concentration and time-dependent manner. We also found chidamide had the cytotoxicity effect on FLT3-ITD positive and negative AML cells. Moreover, with respect to relapsed/refractory patients, chidamide showed the same effectiveness as that in de novo AML patients. Notably, chidamide synergistically enhanced apoptosis caused by cytarabine. Our results support chidamide alone or combine with cytarabine may be used as an alternative therapeutic choice for AML patients especially those with FLT3-ITD mutation or relapsed/refractory ones. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

FLT3-ITD induces expression of Pim kinases through STAT5 to confer resistance to the PI3K/Akt pathway inhibitors on leukemic cells by enhancing the mTORC1/Mcl-1 pathway.

PubMed

Okada, Keigo; Nogami, Ayako; Ishida, Shinya; Akiyama, Hiroki; Chen, Cheng; Umezawa, Yoshihiro; Miura, Osamu

2018-02-06

FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells. These cooperative effects were enhanced or inhibited by knock down of mTOR or expression of its activated mutant, respectively. Overexpression of Mcl-1 conferred the resistance on 32D/ITD cells to combined inhibition of the PI3K/Akt pathway and Pim kinases, while the Mcl-1-specific BH3 mimetic A-1210477 conquered the resistance of MV4-11 cells to GDC-0941. Furthermore, overexpression of Pim-1 in 32D/TKD enhanced the mTORC1/Mcl-1 pathway and partially protected it from the PI3K/Akt inhibitors or the FLT3 inhibitor gilteritinib to confer the resistance to PI3K/Akt inhibitors. Finally, AZD1208 and GDC-0941 cooperatively inhibited the mTORC1/Mcl-1 pathway and reduced viable cell numbers of primary AML cells from some FLT3-ITD positive cases. Thus, Pim kinases may protect the mTORC1/4EBP1/Mcl-1 pathway to confer the resistance to the PI3K/Akt inhibitors on FLT3-ITD cells and represent promising therapeutic targets.

Estimating individual tree mid- and understory rank-size distributions from airborne laser scanning in semi-arid forests

Treesearch

Tyson L. Swetnam; Donald A. Falk; Ann M. Lynch; Stephen R. Yool

2014-01-01

Limitations inherent to airborne laser scanning (ALS) technology and the complex sorting and packing relationships of forests complicate accurate remote sensing of mid- and understory trees, especially in denser forest stands. Self-similarities in rank-sized individual tree distributions (ITD), e.g. bole diameter or height, are a well-understood property of natural,...

Models of the electrically stimulated binaural system: A review.

PubMed

Dietz, Mathias

2016-01-01

In an increasing number of countries, the standard treatment for deaf individuals is moving toward the implantation of two cochlear implants. Today's device technology and fitting procedure, however, appears as if the two implants would serve two independent ears and brains. Many experimental studies have demonstrated that after careful matching and balancing of left and right stimulation in controlled laboratory studies most patients have almost normal sensitivity to interaural level differences and some sensitivity to interaural time differences (ITDs). Mechanisms underlying the limited ITD sensitivity are still poorly understood and many different aspects may contribute. Recent pioneering computational approaches identified some of the functional implications the electric input imposes on the neural brainstem circuits. Simultaneously these studies have raised new questions and certainly demonstrated that further refinement of the model stages is necessary. They join the experimental study's conclusions that binaural device technology, binaural fitting, specific speech coding strategies, and binaural signal processing algorithms are obviously missing components to maximize the benefit of bilateral implantation. Within this review, the existing models of the electrically stimulated binaural system are explained, compared, and discussed from a viewpoint of a "CI device with auditory system" and from that of neurophysiological research.

Detection and localization of sounds: Virtual tones and virtual reality

NASA Astrophysics Data System (ADS)

Zhang, Peter Xinya

Modern physiologically based binaural models employ internal delay lines in the pathways from left and right peripheries to central processing nuclei. Various models apply the delay lines differently, and give different predictions for the detection of dichotic pitches, wherein listeners hear a virtual tone in the noise background. Two dichotic pitch stimuli (Huggins pitch and binaural coherence edge pitch) with low boundary frequencies were used to test the predictions by two different models. The results from five experiments show that the relative dichotic pitch strengths support the equalization-cancellation model and disfavor the central activity pattern (CAP) model. The CAP model makes predictions for the lateralization of Huggins pitch based on interaural time differences (ITD). By measuring human lateralization for Huggins pitches with two different types of phase boundaries (linear-phase and stepped phase), and by comparing with lateralization of sine-tones, it was shown that the lateralization of Huggins pitch stimuli is similar to that of the corresponding sine-tones, and the lateralizations of Huggins pitch stimuli with the two different boundaries were even more similar to one another. The results agreed roughly with the CAP model predictions. Agreement was significantly improved by incorporating individualized scale factors and offsets into the model, and was further unproved with a model including compression at large ITDs. Furthermore, ambiguous stimuli, with an interaural phase difference of 180 degrees, were consistently lateralized on the left or right based on individual asymmetries---which introduces the concept of "earedness". Interaural phase difference (IPD) and interaural time difference (ITD) are two different forms of temporal cues. With varying frequency, an auditory system based on IPD or ITD gives different quantitative predictions on lateralization. A lateralization experiment with sine tones tested whether human auditory system is an IPD-meter or an ITD-meter. Listeners estimated the lateral positions of 50 sine tones with IPDs ranging from -150° to +150° and with different frequencies, all in the range where signal fine structure supports lateralization. The estimates indicated that listeners lateralize sine tones on the basis of ITD and not IPD. In order to distinguish between sound sources in front and in back, listeners use spectral cues caused by the diffraction by pinna, head, neck and torso. To study this effect, the VRX technique was developed based on transaural technology. The technique was successful in presenting desired spectra into listeners' ears with high accuracy up to 16 kHz. When presented with real source and simulated virtual signal, listeners in an anechoic room could not distinguish between them. Eleven experiments on discrimination between front and back sources were carried out in an anechoic room. The results show several findings. First, the results support a multiple band comparison model, and disfavor a necessary band(s) model. Second, it was found that preserving the spectral dips was more important than preserving the spectral peaks for successful front/back discrimination. Moreover, it was confirmed that neither monaural cues nor interaural spectral level difference cues were adequate for front/back discrimination. Furthermore, listeners' performance did not deteriorate when presented with sharpened spectra. Finally, when presented with an interaural delay less than 200 mus, listeners could succeed to discriminate front from back, although the image was pulled to the side, which suggests that the localizations in azimuthal plane and in sagittal plane are independent within certain limits.

Audiometric asymmetry and tinnitus laterality.

PubMed

Tsai, Betty S; Sweetow, Robert W; Cheung, Steven W

2012-05-01

To identify an optimal audiometric asymmetry index for predicting tinnitus laterality. Retrospective medical record review. Data from adult tinnitus patients (80 men and 44 women) were extracted for demographic, audiometric, tinnitus laterality, and related information. The main measures were sensitivity, specificity, positive predictive value (PPV), and receiver operating characteristic (ROC) curves. Three audiometric asymmetry indices were constructed using one, two, or three frequency elements to compute the average interaural threshold difference (aITD). Tinnitus laterality predictive performance of a particular index was assessed by increasing the cutoff or minimum magnitude of the aITD from 10 to 35 dB in 5-dB steps to determine its ROC curve. Single frequency index performance was inferior to the other two (P < .05). Double and triple frequency indices were indistinguishable (P > .05). Two adjoining frequency elements with aITD ≥ 15 dB performed optimally for predicting tinnitus laterality (sensitivity = 0.59, specificity = 0.71, and PPV = 0.76). Absolute and relative magnitudes of hearing loss in the poorer ear were uncorrelated with tinnitus distress. An optimal audiometric asymmetry index to predict tinnitus laterality is one whereby 15 dB is the minimum aITD of two adjoining frequencies, inclusive of the maximal ITD. Tinnitus laterality dependency on magnitude of interaural asymmetry may inform design and interpretation of neuroimaging studies. Monaural acoustic tinnitus therapy may be an initial consideration for asymmetric hearing loss meeting the criterion of aITD ≥ 15 dB. Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

An arch-shaped intraoral tongue drive system with built-in tongue-computer interfacing SoC.

PubMed

Park, Hangue; Ghovanloo, Maysam

2014-11-14

We present a new arch-shaped intraoral Tongue Drive System (iTDS) designed to occupy the buccal shelf in the user's mouth. The new arch-shaped iTDS, which will be referred to as the iTDS-2, incorporates a system-on-a-chip (SoC) that amplifies and digitizes the raw magnetic sensor data and sends it wirelessly to an external TDS universal interface (TDS-UI) via an inductive coil or a planar inverted-F antenna. A built-in transmitter (Tx) employs a dual-band radio that operates at either 27 MHz or 432 MHz band, according to the wireless link quality. A built-in super-regenerative receiver (SR-Rx) monitors the wireless link quality and switches the band if the link quality is below a predetermined threshold. An accompanying ultra-low power FPGA generates data packets for the Tx and handles digital control functions. The custom-designed TDS-UI receives raw magnetic sensor data from the iTDS-2, recognizes the intended user commands by the sensor signal processing (SSP) algorithm running in a smartphone, and delivers the classified commands to the target devices, such as a personal computer or a powered wheelchair. We evaluated the iTDS-2 prototype using center-out and maze navigation tasks on two human subjects, which proved its functionality. The subjects' performance with the iTDS-2 was improved by 22% over its predecessor, reported in our earlier publication.

RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia.

PubMed

Hospital, M-A; Jacquel, A; Mazed, F; Saland, E; Larrue, C; Mondesir, J; Birsen, R; Green, A S; Lambert, M; Sujobert, P; Gautier, E-F; Salnot, V; Le Gall, M; Decroocq, J; Poulain, L; Jacque, N; Fontenay, M; Kosmider, O; Récher, C; Auberger, P; Mayeux, P; Bouscary, D; Sarry, J-E; Tamburini, J

2018-03-01

Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90 kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML.

Separation of concurrent broadband sound sources by human listeners

NASA Astrophysics Data System (ADS)

Best, Virginia; van Schaik, André; Carlile, Simon

2004-01-01

The effect of spatial separation on the ability of human listeners to resolve a pair of concurrent broadband sounds was examined. Stimuli were presented in a virtual auditory environment using individualized outer ear filter functions. Subjects were presented with two simultaneous noise bursts that were either spatially coincident or separated (horizontally or vertically), and responded as to whether they perceived one or two source locations. Testing was carried out at five reference locations on the audiovisual horizon (0°, 22.5°, 45°, 67.5°, and 90° azimuth). Results from experiment 1 showed that at more lateral locations, a larger horizontal separation was required for the perception of two sounds. The reverse was true for vertical separation. Furthermore, it was observed that subjects were unable to separate stimulus pairs if they delivered the same interaural differences in time (ITD) and level (ILD). These findings suggested that the auditory system exploited differences in one or both of the binaural cues to resolve the sources, and could not use monaural spectral cues effectively for the task. In experiments 2 and 3, separation of concurrent noise sources was examined upon removal of low-frequency content (and ITDs), onset/offset ITDs, both of these in conjunction, and all ITD information. While onset and offset ITDs did not appear to play a major role, differences in ongoing ITDs were robust cues for separation under these conditions, including those in the envelopes of high-frequency channels.

Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases

PubMed Central

Schmidt-Arras, Dirk-E.; Böhmer, Annette; Markova, Boyka; Choudhary, Chunaram; Serve, Hubert; Böhmer, Frank-D.

2005-01-01

Constitutive activation of receptor tyrosine kinases (RTKs) is a frequent event in human cancer cells. Activating mutations in Fms-like tyrosine kinase 3 (FLT-3), notably, internal tandem duplications in the juxtamembrane domain (FLT-3 ITD), have been causally linked to acute myeloid leukemia. As we describe here, FLT-3 ITD exists predominantly in an immature, underglycosylated 130-kDa form, whereas wild-type FLT-3 is expressed predominantly as a mature, complex glycosylated 150-kDa molecule. Endogenous FLT-3 ITD, but little wild-type FLT-3, is detectable in the endoplasmic reticulum (ER) compartment. Conversely, cell surface expression of FLT-3 ITD is less efficient than that of wild-type FLT-3. Inhibition of FLT-3 ITD kinase by small molecules, inactivating point mutations, or coexpression with the protein-tyrosine phosphatases (PTPs) SHP-1, PTP1B, and PTP-PEST but not RPTPα promotes complex glycosylation and surface localization. However, PTP coexpression has no effect on the maturation of a surface glycoprotein of vesicular stomatitis virus. The maturation of wild-type FLT-3 is impaired by general PTP inhibition or by suppression of endogenous PTP1B. Enhanced complex formation of FLT-3 ITD with the ER-resident chaperone calnexin indicates that its retention in the ER is related to inefficient folding. The regulation of RTK maturation by tyrosine phosphorylation was observed with other RTKs as well, defines a possible role for ER-resident PTPs, and may be related to the altered signaling quality of constitutively active, transforming RTK mutants. PMID:15831474

Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy.

PubMed

Pratcorona, Marta; Brunet, Salut; Nomdedéu, Josep; Ribera, Josep Maria; Tormo, Mar; Duarte, Rafael; Escoda, Lourdes; Guàrdia, Ramon; Queipo de Llano, M Paz; Salamero, Olga; Bargay, Joan; Pedro, Carmen; Martí, Josep Maria; Torrebadell, Montserrat; Díaz-Beyá, Marina; Camós, Mireia; Colomer, Dolors; Hoyos, Montserrat; Sierra, Jorge; Esteve, Jordi

2013-04-04

Risk associated to FLT3 internal tandem duplication (FLT3-ITD) in patients with acute myeloid leukemia (AML) may depend on mutational burden and its interaction with other mutations. We analyzed the effect of FLT3-ITD/FLT3 wild-type (FLT3wt) ratio depending on NPM1 mutation (NPM1mut) in 303 patients with intermediate-risk cytogenetics AML treated with intensive chemotherapy. Among NPM1mut patients, FLT3wt and low ratio (<0.5) subgroups showed similar overall survival, relapse risk, and leukemia-free survival, whereas high ratio (≥0.5) patients had a worse outcome. In NPM1wt AML, FLT3-ITD subgroups showed a comparable outcome, with higher risk of relapse and shortened overall survival than FLT3wt patients. Allogeneic stem cell transplantation in CR1 was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1mut AML with absent or low ratio FLT3-ITD. In conclusion, effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio.

Matrix isolation with an ion transfer device for interference-free simultaneous spectrophotometric determinations of hexavalent and trivalent chromium in a flow-based system.

PubMed

Ohira, Shin-Ichi; Nakamura, Koretaka; Chiba, Mitsuki; Dasgupta, Purnendu K; Toda, Kei

2017-03-01

Chromium speciation by spectrophotometric determination of hexavalent chromium (Cr(VI)) with diphenylcarbazide (DPC) has several problems. These include: (1) the inability to directly detect trivalent chromium (Cr(III)) with DPC, (2) positive interference in Cr(VI) determination by other metal cations and (3) negative interference by any reducing agent present in the sample. These are addressed with an ion transfer device (ITD) in a flow injection analysis system. We previously developed the ITD for electrodialytic separations. Here we separate oppositely charged Cr(III) and Cr(VI) species by the ITD into two different acceptor solutions within ~5 s. The acceptor solutions consist of buffered H 2 O 2 to oxidize the Cr(III) to Cr(VI). Then DPC is added to either acceptor to measure Cr(III) and Cr(VI) spectrophotometrically. The system was optimized to provide the same response for Cr(VI) and Cr(III) with limits of detection (LODs, S/N=3) of 0.5 μg L -1 for each and a throughput rate of 30 samples h -1 . The ITD separation was also effective for matrix isolation and reduction of interferences. Potential cationic interferences were not transferred into the anionic Cr(VI) acceptor stream. Much of the organic compounds in soil extracts were also eliminated as evidenced from standard addition and recovery studies. Copyright © 2016 Elsevier B.V. All rights reserved.

STAT5 Is Crucial to Maintain Leukemic Stem Cells in Acute Myelogenous Leukemias Induced by MOZ-TIF2

PubMed Central

Tam, Winnie F.; Hähnel, Patricia S.; Schüler, Andrea; Lee, Benjamin H.; Okabe, Rachel; Zhu, Nan; Pante, Saskia V.; Raffel, Glen; Mercher, Thomas; Wernig, Gerlinde; Bockamp, Ernesto; Sasca, Daniel; Kreft, Andreas; Robinson, Gertraud W.; Hennighausen, Lothar; Gilliland, D. Gary; Kindler, Thomas

2014-01-01

MOZ-TIF2 is a leukemogenic fusion oncoprotein that confers self-renewal capability to hematopoietic progenitor cells and induces acute myelogenous leukemia (AML) with long latency in bone marrow transplantation assays. Here, we report that FLT3-ITD transforms hematopoietic cells in cooperation with MOZ-TIF2 in vitro and in vivo. Coexpression of FLT3-ITD confers growth factor independent survival/proliferation, shortens disease latency, and results in an increase in the number of leukemic stem cells (LSC). We show that STAT5, a major effector of aberrant FLT3-ITD signal transduction, is both necessary and sufficient for this cooperative effect. In addition, STAT5 signaling is essential for MOZ-TIF2–induced leukemic transformation itself. Lack of STAT5 in fetal liver cells caused rapid differentiation and loss of replating capacity of MOZ-TIF2–transduced cells enriched for LSCs. Furthermore, mice serially transplanted with Stat5−/− MOZ-TIF2 leukemic cells develop AML with longer disease latency and finally incomplete penetrance when compared with mice transplanted with Stat5+/+ MOZ-TIF2 leukemic cells. These data suggest that STAT5AB is required for the self-renewal of LSCs and represents a combined signaling node of FLT3-ITD and MOZ-TIF2 driven leukemogenesis. Therefore, targeting aberrantly activated STAT5 or rewired downstream signaling pathways may be a promising therapeutic option. PMID:23149921

Functional Pathway Analysis Using SCNP of FLT3 Receptor Pathway Deregulation in AML Provides Prognostic Information Independent from Mutational Status

PubMed Central

Cesano, Alessandra; Putta, Santosh; Rosen, David B.; Cohen, Aileen C.; Gayko, Urte; Mathi, Kavita; Woronicz, John; Hawtin, Rachael E.; Cripe, Larry; Sun, Zhuoxin; Tallman, Martin S.; Paietta, Elisabeth

2013-01-01

FMS-like tyrosine kinase 3 receptor (FLT3) internal tandem duplication (ITD) mutations result in constitutive activation of this receptor and have been shown to increase the risk of relapse in patients with acute myeloid leukemia (AML); however, substantial heterogeneity in clinical outcomes still exists within both the ITD mutated and unmutated AML subgroups, suggesting alternative mechanisms of disease relapse not accounted by FLT3 mutational status. Single cell network profiling (SCNP) is a multiparametric flow cytometry based assay that simultaneously measures, in a quantitative fashion and at the single cell level, both extracellular surface marker levels and changes in intracellular signaling proteins in response to extracellular modulators. We previously reported an initial characterization of FLT3 ITD-mediated signaling using SCNP. Herein SCNP was applied sequentially to two separate cohorts of samples collected from elderly AML patients at diagnosis. In the first (training) study, AML samples carrying unmutated, wild-type FLT3 (FLT3 WT) displayed a wide range of induced signaling, with a fraction having signaling profiles comparable to FLT3 ITD AML samples. Conversely, the FLT3 ITD AML samples displayed more homogeneous induced signaling, with the exception of patients with low (<40%) mutational load, which had profiles comparable to FLT3 WT AML samples. This observation was then confirmed in an independent (verification) cohort. Data from the second cohort were also used to assess the association between SCNP data and disease-free survival (DFS) in the context of FLT3 and nucleophosmin (NPM1) mutational status among patients who achieved complete remission (CR) to induction chemotherapy. The combination of SCNP read outs together with FLT3 and NPM1 molecular status improved the DFS prediction accuracy of the latter. Taken together, these results emphasize the value of comprehensive functional assessment of biologically relevant signaling pathways in AML as a basis for the development of highly predictive tests for guidance of post-remission therapy. PMID:23431389

Trading of dynamic interaural time and level difference cues and its effect on the auditory motion-onset response measured with electroencephalography.

PubMed

Altmann, Christian F; Ueda, Ryuhei; Bucher, Benoit; Furukawa, Shigeto; Ono, Kentaro; Kashino, Makio; Mima, Tatsuya; Fukuyama, Hidenao

2017-10-01

Interaural time (ITD) and level differences (ILD) constitute the two main cues for sound localization in the horizontal plane. Despite extensive research in animal models and humans, the mechanism of how these two cues are integrated into a unified percept is still far from clear. In this study, our aim was to test with human electroencephalography (EEG) whether integration of dynamic ITD and ILD cues is reflected in the so-called motion-onset response (MOR), an evoked potential elicited by moving sound sources. To this end, ITD and ILD trajectories were determined individually by cue trading psychophysics. We then measured EEG while subjects were presented with either static click-trains or click-trains that contained a dynamic portion at the end. The dynamic part was created by combining ITD with ILD either congruently to elicit the percept of a right/leftward moving sound, or incongruently to elicit the percept of a static sound. In two experiments that differed in the method to derive individual dynamic cue trading stimuli, we observed an MOR with at least a change-N1 (cN1) component for both the congruent and incongruent conditions at about 160-190 ms after motion-onset. A significant change-P2 (cP2) component for both the congruent and incongruent ITD/ILD combination was found only in the second experiment peaking at about 250 ms after motion onset. In sum, this study shows that a sound which - by a combination of counter-balanced ITD and ILD cues - induces a static percept can still elicit a motion-onset response, indicative of independent ITD and ILD processing at the level of the MOR - a component that has been proposed to be, at least partly, generated in non-primary auditory cortex. Copyright © 2017 Elsevier Inc. All rights reserved.

Idaho Transportation Department 2011 customer satisfaction survey.

DOT National Transportation Integrated Search

2011-10-01

In the spring and summer of 2011, the Idaho Transportation Department (ITD) commissioned a statewide customer satisfaction survey of Idaho residents to assess their perception of ITDs performance in several key areas of customer service. The areas...

Directional hearing by linear summation of binaural inputs at the medial superior olive

PubMed Central

van der Heijden, Marcel; Lorteije, Jeannette A. M.; Plauška, Andrius; Roberts, Michael T.; Golding, Nace L.; Borst, J. Gerard G.

2013-01-01

SUMMARY Neurons in the medial superior olive (MSO) enable sound localization by their remarkable sensitivity to submillisecond interaural time differences (ITDs). Each MSO neuron has its own “best ITD” to which it responds optimally. A difference in physical path length of the excitatory inputs from both ears cannot fully account for the ITD tuning of MSO neurons. As a result, it is still debated how these inputs interact and whether the segregation of inputs to opposite dendrites, well-timed synaptic inhibition, or asymmetries in synaptic potentials or cellular morphology further optimize coincidence detection or ITD tuning. Using in vivo whole-cell and juxtacellular recordings, we show here that ITD tuning of MSO neurons is determined by the timing of their excitatory inputs. The inputs from both ears sum linearly, whereas spike probability depends nonlinearly on the size of synaptic inputs. This simple coincidence detection scheme thus makes accurate sound localization possible. PMID:23764292

Anatomical limits on interaural time differences: an ecological perspective

PubMed Central

Hartmann, William M.; Macaulay, Eric J.

2013-01-01

Human listeners, and other animals too, use interaural time differences (ITD) to localize sounds. If the sounds are pure tones, a simple frequency factor relates the ITD to the interaural phase difference (IPD), for which there are known iso-IPD boundaries, 90°, 180°… defining regions of spatial perception. In this article, iso-IPD boundaries for humans are translated into azimuths using a spherical head model (SHM), and the calculations are checked by free-field measurements. The translated boundaries provide quantitative tests of an ecological interpretation for the dramatic onset of ITD insensitivity at high frequencies. According to this interpretation, the insensitivity serves as a defense against misinformation and can be attributed to limits on binaural processing in the brainstem. Calculations show that the ecological explanation passes the tests only if the binaural brainstem properties evolved or developed consistent with heads that are 50% smaller than current adult heads. Measurements on more realistic head shapes relax that requirement only slightly. The problem posed by the discrepancy between the current head size and a smaller, ideal head size was apparently solved by the evolution or development of central processes that discount large IPDs in favor of interaural level differences. The latter become more important with increasing head size. PMID:24592209

Numerical investigation of the effects of ITD length on low pressure nozzle

NASA Astrophysics Data System (ADS)

Liu, Guang; Liu, Jun; Liu, Hongrui; Wang, Pei; Du, Qiang

2017-06-01

The advantage of high efficiency, low SFC (Specific Fuel Consumption), ultra-high bypass ratio turbofan engine attracts more and more attention in modern commercial engine. The intermediate turbine duct (ITD), which connects high pressure turbine (HPT) with low pressure turbine (LPT), has a critical impact on the overall performance of turbine by guiding flow coming from HPT to LPT without too much loss. Therefore, it becomes more and more urgent to master the technique of designing aggressive, even super-aggressive ITD. Much more concerns have been concentrated on the duct. However, in order to further improve turbine, LPT nozzle is arranged into ITD to shorten low pressure axle. With such design concept, it is obvious that LPT nozzle flow field is easily influenced by upstream duct structure, but receives much less interests on the contrary. In this paper, numerical method is used to investigate the effects of length of ITD with upstream swirl blades on LPT nozzle. Nine models with the same swirl and nozzle blades, while the length of ITD is the only parameter to be changed, will be discussed. Finally, several conclusions and advices for designers are summarized. After changing axial length of ducts, inlet and outlet flow field of nozzle differs, correspondingly. On the other hand, the shearing stress on nozzle blade (suction and pressure) surface presents individual feature under various inlet flow. In addition to that, "Clocking-like effect" is described in this paper, which will contribute much to the pressure loss and should be paid enough attention.

Intratympanic treatment of intractable unilateral Meniere disease: gentamicin or dexamethasone? A randomized controlled trial.

PubMed

Casani, Augusto Pietro; Piaggi, Paolo; Cerchiai, Niccolò; Seccia, Veronica; Franceschini, Stefano Sellari; Dallan, Iacopo

2012-03-01

To determine the efficacy and safety of low-dose intratympanic gentamicin (ITG) compared with intratympanic dexamethasone (ITD) in patients with intractable unilateral Ménière disease (MD). Open prospective randomized controlled study. Tertiary referral center. Sixty patients affected by definite unilateral MD were enrolled between January 1, 2007, and June 30, 2008. Thirty-two patients were treated with a buffered gentamicin solution injected in the middle ear (maximum of 2 injections); 28 patients were treated with ITD (4 mg/mL, 3 injections at intervals of 1 every 3 days). Mean outcome measurements consisted of control of vertigo attacks, pure tone average (PTA), speech discrimination score, functional disability score, and statistical analysis using repeated measures analysis of variance. In the ITG group at 2-year follow-up, complete control of vertigo (class A) was achieved in 26 patients (81%) and substantial control of vertigo (class B) in 4 patients (12.5%). In the ITD group, class A was achieved in 12 (43%), and class B in 5 (18%) patients. In the gentamicin group, 4 patients showed a reduction in PTA of ≥10 dB. In the ITD group, PTA was unchanged or slightly improved in 16 patients (belonging to class A-B) and worse in 12. Low-dose ITG achieved better outcome than ITD in the control of vertigo attacks in patients suffering from unilateral MD, with a very low incidence of hearing deterioration. ITD offers poorer vertigo control rate, and hearing preservation is achieved only in cases with no vertigo recurrences.

Numerical investigation of the effects of rising angle on intermediate turbine duct and nearby turbines

NASA Astrophysics Data System (ADS)

Liu, Hongrui; Ji, Lucheng; Liu, Jun; Du, Qiang; Liu, Guang; Wang, Pei; Du, Meimei

2017-10-01

In order to improve the efficiency, ultra-high bypass ratio engine attracts more and more attention because of its huge advantage, which has larger diameter low pressure turbine (LPT). This trend will lead to aggressive (high diffusion) intermediate turbine duct (ITD) design. It is necessary to guide the flow leaving high pressure turbine (HPT) to LPT at a larger diameter without any severe loss generating separation or flow disturbances. In this paper, eight ITDs with upstream swirl vanes and downstream LPT nozzle are investigated with the aid of numerical method. These models are modified from a unique ITD prototype, which comes from a real engine. Key parameters like area ratio, inlet height, and non-dimensional length of the ITDs are kept unchanged, while the rising angle (radial offset) is the only changed parameter which ranges from 8 degrees to 45 degrees. In this paper, the effects of rising angle (RA) on ITD, as well as nearby turbines, will be analyzed in detail. According to the investigation results, RA could be as large as 40 degrees in such model of this paper to escape separation; When RA increases, local inlet flow field of LPT nozzle appears to be with apparent variation; while a positive result is that outlet flow field could be kept almost unchanged through modifying blade profile. On the other hand, it seems optimistic that the overall total pressure loss could be kept nearly equivalent among different RA cases. And a valuable conclusion is that outer wall curvature is more important for pressure loss, which advises a clear direction for optimizing ITD.

Evaluation of the Idaho Transportation Department integrated road-weather information system

DOT National Transportation Integrated Search

2005-02-02

This report presents the results of FHWA's evaluation of the Idaho Transportation Department's (ITD) integration of its Road-Weather Information System (RWIS). The ITD RWIS project was selected for evaluation because it held significant potential to ...

Use of impedance threshold device in conjunction with our novel adhesive glove device for ACD-CPR does not result in additional chest decompression.

PubMed

Shih, Andre; Udassi, Sharda; Porvasnik, Stacy L; Lamb, Melissa A; Badugu, Srinivasarao; Venkata, Giridhar Kaliki; Lopez-Colon, Dalia; Haque, Ikram U; Zaritsky, Arno L; Udassi, Jai P

2013-10-01

To evaluate the hemodynamic effects of using an adhesive glove device (AGD) to perform active compression-decompression CPR (AGD-CPR) in conjunction with an impedance threshold device (ITD) in a pediatric cardiac arrest model. Controlled, randomized animal study. In this study, 18 piglets were anesthetized, ventilated, and continuously monitored. After 3min of untreated ventricular fibrillation, animals were randomized (6/group) to receive either standard CPR (S-CPR), active compression-decompression CPR via adhesive glove device (AGD-CPR) or AGD-CPR along with an ITD (AGD-CPR+ITD) for 2min at 100-120compressions/min. AGD is delivered using a fingerless leather glove with a Velcro patch on the palmer aspect and the counter Velcro patch adhered to the pig's chest. Data (mean±SD) were analyzed using one-way ANOVA with pair wise multiple comparisons to assess differences between groups. p-Value≤0.05 was considered significant. Both AGD-CPR and AGD-CPR+ITD groups produced lower intrathoracic pressure (IttP, mmHg) during decompression phase (-13.4±6.7, p=0.01 and -11.9±6.5, p=0.01, respectively) in comparison to S-CPR (-0.3±4.2). Carotid blood flow (CBF, % of baseline mL/min) was higher in AGD-CPR and AGD-CPR+ITD (respectively 64.3±47.3%, p=0.03 and 67.5±33.1%, p=0.04) as compared with S-CPR (29.1±12.5%). Coronary perfusion pressure (CPP, mmHg) was higher in AGD-CPR and AGD-CPR+ITD (respectively 19.7±4.6, p=0.04 and 25.6±12.1, p=0.02) when compared to S-CPR (9.6±9.1). There was no statistically significant difference between AGD-CPR and AGD-CPR+ITD groups with reference to intra-thoracic pressure, carotid blood flow and coronary perfusion pressure. Active compression decompression delivered by this simple and inexpensive adhesive glove device resulted in improved cerebral blood flow and coronary perfusion pressure. There was no statistically significant added effect of ITD use along with AGD-CPR on the decompression of the chest. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Assessment of an Electronic Intervention in Young Women with Heavy Menstrual Bleeding.

PubMed

Dietrich, Jennifer E; Yee, Donald L; Santos, Xiomara M; Bercaw-Pratt, Jennifer L; Kurkowski, Jennifer; Soni, Heather; Lee-Kim, Youngna J; Shah, Mona D; Mahoney, Donald; Srivaths, Lakshmi V

2017-04-01

STUDY OBJECTIVE, DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Bleeding disorders (BD) occur in up to 50% of adolescents with heavy menstrual bleeding (HMB). This presents unique challenges to health care providers because of the complexity of treating the condition and such complexity can result in difficulty with patients understanding basic information about their condition, limit communication with medical providers, and patient compliance. The aim of the study was to use an electronic approach to enhance patient compliance with medications used to treat their HMB, and to provide educational access to adolescents with BD. This was a prospective cohort study involving patients in a Young Women's Bleeding Disorder Clinic at a single children's hospital. Subjects were given an iPod Touch (Apple Inc, Cupertino, CA) device (ITD), preloaded with the iPeriod (Winkpass Creations) application. Participants recorded information about their BD that they learned about on BD Web sites, and menses, and medications. Electronic and charted data were collected to monitor compliance with prescribed treatment regimens. All ITD allowed Wi-Fi access to allow teens to explore BD Web sites and knowledge was assessed. Twenty-three of 45 subjects completed the study. The mean age was 14.1 ± 1.9 years. Subjects who were compliant with the ITD (group 1), charted on baseline symptoms, menstrual flow (83.3%), cramps (100%, 23/23), breakthrough bleeding (95.6%, 22/23), mood (95.6%, 22/23), and medication use (91.7%) for a mean of 9.3 ± 3.1 months. Subjects who were nonusers (group 2) did not report on symptoms, their condition, or medication use in the device (n = 22). More than 75% (17/23) of subjects in group 1 used hormones alone or hormones with antifibrinolytic agents to control HMB. No subjects stopped or missed medications who were in group 1 intentionally, and also there were 9 enrollees within this same group who missed a medication related to awaiting the prescription to be filled from pharmacy. In group 2, 17 enrollees missed medications, resulting in 19% (4/22) of these enrollees being admitted to hospital for 1-2 days. In addition, enrollees in group 2 missed more medications on average compared with group 1. No subjects in group 1 required admission for HMB treatment failure during the study period, compared with those in group 2 (P = .006). All subjects in group 1 reported accessing Web sites using their ITD to learn about their BD. Groups 1 and 2 did not differ in the number of medications that were prescribed during the time frame (P = .77) or the number of follow-up clinic visits (P = .49). Furthermore, those in group 1 reported fewer breakthrough bleeding episodes than those in group 2 according to clinic notes (P = .03). Users of the ITD were given a set of knowledge questions. Group 2 subjects were not consistent users of the ITD use and did not complete the knowledge questions. Group 1 and 2 could not be compared with regard to knowledge as a result. ITD is an excellent tool for adolescents with HMB and BD to allow self-monitoring, provider monitoring, and improve educational access through engaging technology; compliance with device use was associated with several parameters suggestive of improved clinical outcomes. Copyright © 2016 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.

The effect of bridge deck design methodology on crack control.

DOT National Transportation Integrated Search

2010-01-30

At present, the Idaho Transportation Department (ITD) Bridge Design Manual allows engineers to use the AASHTO empirical method to : design concrete bridge decks. However, the ITD Bridge Section would like to compare their design practices to those em...

Identification of pyrrolo[2,3-d]pyrimidines as potent HCK and FLT3-ITD dual inhibitors.

PubMed

Koda, Yasuko; Kikuzato, Ko; Mikuni, Junko; Tanaka, Akiko; Yuki, Hitomi; Honma, Teruki; Tomabechi, Yuri; Kukimoto-Niino, Mutsuko; Shirouzu, Mikako; Shirai, Fumiyuki; Koyama, Hiroo

2017-11-15

A series of novel pyrrolo[2,3-d]pyrimidines were synthesized by introducing 15 different amino acids to 7-cyclohexyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. Compounds with potent activities against HCK and FLT3-ITD were evaluated in viability studies with acute myeloid leukemia cell line MV4-11. Our structure activity relationship analyses lead to the identification of compound 31, which exhibited potent HCK and FLT3-ITD inhibition and activity against the MV4-11 cell line. Copyright © 2017 Elsevier Ltd. All rights reserved.

Calibration of the Diameter Distribution Derived from the Area-based Approach with Individual Tree-based Diameter Estimates Using the Airborne Laser Scanning

NASA Astrophysics Data System (ADS)

Xu, Q.; Hou, Z.; Maltamo, M.; Tokola, T.

2015-12-01

Diameter distributions of trees are important indicators of current forest stand structure and future dynamics. A new method was proposed in the study to combine the diameter distributions derived from the area-based approach (ABA) and the diameter distribution derived from the individual tree detection (ITD) in order to obtain more accurate forest stand attributes. Since dominant trees can be reliably detected and measured by the Lidar data via the ITD, the focus of the study is to retrieve the suppressed trees (trees that were missed by the ITD) from the ABA. Replacement and histogram matching were respectively employed at the plot level to retrieve the suppressed trees. Cut point was detected from the ITD-derived diameter distribution for each sample plot to distinguish dominant trees from the suppressed trees. The results showed that calibrated diameter distributions were more accurate in terms of error index and the entire growing stock estimates. Compared with the best performer between the ABA and the ITD, calibrated diameter distributions decreased the relative RMSE of the estimated entire growing stock, saw log and pulpwood fractions by 2.81%, 3.05% and 7.73% points respectively. Calibration improved the estimation of pulpwood fraction significantly, resulting in a negligible bias of the estimated entire growing stock.

Lateralization of noise-burst trains based on onset and ongoing interaural delays.

PubMed

Freyman, Richard L; Balakrishnan, Uma; Zurek, Patrick M

2010-07-01

The lateralization of 250-ms trains of brief noise bursts was measured using an acoustic pointing technique. Stimuli were designed to assess the contribution of the interaural time delay (ITD) of the onset binaural burst relative to that of the ITDs in the ongoing part of the train. Lateralization was measured by listeners' adjustments of the ITD of a pointer stimulus, a 50-ms burst of noise, to match the lateral position of the target train. Results confirmed previous reports of lateralization dominance by the onset burst under conditions in which the train is composed of frozen tokens and the ongoing part contains multiple ambiguous interaural delays. In contrast, lateralization of ongoing trains in which fresh noise tokens were used for each set of two alternating (left-leading/right-leading) binaural pairs followed the ITD of the first pair in each set, regardless of the ITD of the onset burst of the entire stimulus and even when the onset burst was removed by gradual gating. This clear lateralization of a long-duration stimulus with ambiguous interaural delay cues suggests precedence mechanisms that involve not only the interaural cues at the beginning of a sound, but also the pattern of cues within an ongoing sound.

Speech segregation based-on binaural cue: interaural time difference (itd) and interaural level difference (ild)

NASA Astrophysics Data System (ADS)

Nur Farid, Mifta; Arifianto, Dhany

2016-11-01

A person who is suffering from hearing loss can be helped by using hearing aids and the most optimal performance of hearing aids are binaural hearing aids because it has similarities to human auditory system. In a conversation at a cocktail party, a person can focus on a single conversation even though the background sound and other people conversation is quite loud. This phenomenon is known as the cocktail party effect. In an early study, has been explained that binaural hearing have an important contribution to the cocktail party effect. So in this study, will be performed separation on the input binaural sound with 2 microphone sensors of two sound sources based on both the binaural cue, interaural time difference (ITD) and interaural level difference (ILD) using binary mask. To estimate value of ITD, is used cross-correlation method which the value of ITD represented as time delay of peak shifting at time-frequency unit. Binary mask is estimated based on pattern of ITD and ILD to relative strength of target that computed statistically using probability density estimation. Results of sound source separation performing well with the value of speech intelligibility using the percent correct word by 86% and 3 dB by SNR.

Blind people are more sensitive than sighted people to binaural sound-location cues, particularly inter-aural level differences.

PubMed

Nilsson, Mats E; Schenkman, Bo N

2016-02-01

Blind people use auditory information to locate sound sources and sound-reflecting objects (echolocation). Sound source localization benefits from the hearing system's ability to suppress distracting sound reflections, whereas echolocation would benefit from "unsuppressing" these reflections. To clarify how these potentially conflicting aspects of spatial hearing interact in blind versus sighted listeners, we measured discrimination thresholds for two binaural location cues: inter-aural level differences (ILDs) and inter-aural time differences (ITDs). The ILDs or ITDs were present in single clicks, in the leading component of click pairs, or in the lagging component of click pairs, exploiting processes related to both sound source localization and echolocation. We tested 23 blind (mean age = 54 y), 23 sighted-age-matched (mean age = 54 y), and 42 sighted-young (mean age = 26 y) listeners. The results suggested greater ILD sensitivity for blind than for sighted listeners. The blind group's superiority was particularly evident for ILD-lag-click discrimination, suggesting not only enhanced ILD sensitivity in general but also increased ability to unsuppress lagging clicks. This may be related to the blind person's experience of localizing reflected sounds, for which ILDs may be more efficient than ITDs. On the ITD-discrimination tasks, the blind listeners performed better than the sighted age-matched listeners, but not better than the sighted young listeners. ITD sensitivity declines with age, and the equal performance of the blind listeners compared to a group of substantially younger listeners is consistent with the notion that blind people's experience may offset age-related decline in ITD sensitivity. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

FLT3 and JAK2 Mutations in Acute Myeloid Leukemia Promote Interchromosomal Homologous Recombination and the Potential for Copy Neutral Loss of Heterozygosity.

PubMed

Gaymes, Terry J; Mohamedali, Azim; Eiliazadeh, Anthony L; Darling, David; Mufti, Ghulam J

2017-04-01

Acquired copy neutral LOH (CN-LOH) is a frequent occurrence in myeloid malignancies and is often associated with resistance to standard therapeutic modalities and poor survival. Here, we show that constitutive signaling driven by mutated FLT3 and JAK2 confers interchromosomal homologous recombination (iHR), a precedent for CN-LOH. Using a targeted recombination assay, we determined significant iHR activity in internal tandem duplication FLT3 (FLT3-ITD) and JAK2V617F-mutated cells. Sister chromatid exchanges, a surrogate measure of iHR, was significantly elevated in primary FLT3-ITD normal karyotype acute myeloid leukemia (NK-AML) compared with wild-type FLT3 NK-AML. HR was harmonized to S phase of the cell cycle to repair broken chromatids and prevent iHR. Increased HR activity in G 0 arrested primary FLT3-ITD NK-AML in contrast to wild-type FLT3 NK-AML. Cells expressing mutated FLT3-ITD demonstrated a relative increase in mutation frequency as detected by thymidine kinase (TK) gene mutation assay. Moreover, resistance was associated with CN-LOH at the TK locus. Treatment of FLT3-ITD- and JAK2V617F-mutant cells with the antioxidant N -acetylcysteine diminished reactive oxygen species (ROS), restoring iHR and HR levels. Our findings show that mutated FLT3-ITD and JAK2 augment ROS production and HR, shifting the cellular milieu toward illegitimate recombination events such as iHR and CN-LOH. Therapeutic reduction of ROS may thus prevent leukemic progression and relapse in myeloid malignancies. Cancer Res; 77(7); 1697-708. ©2017 AACR . ©2017 American Association for Cancer Research.

The Crop Evaluation Research for Environmental Strategies (CERES) Remote Sensing 2008 Project Activities

NASA Technical Reports Server (NTRS)

Casas, Joseph C.; Glaser, John A.; Copenhaver, Kenneth L.; May, George

2009-01-01

In recent years, the use of Plant Incorporated Protectant (PIP) corn by American producers has been increasing dramatically. PIP corn contains genetically inserted traits that produce toxins in the plant that provide narrowly targeted protection against specific insect pests. The plant producing t oxms can offer significant reductions in the application of broad -spectrum pesticides that have ecological and human health consequences. PIP corn as a percentage of total corn acreage planted in the US is expected to continue to increase as these protective traits are "stacked" with other desirable traits by seed companies, and producers are seeing considerable increases in corn yield as a result. The introduction of corn as a bio-fuel source for ethanol has increased production by over 6 million hectares in 2007. The United States Environmental Protection Agency (USEPA), which is responsible for the registration of PIP crops under the Federal Insecticide, Fungicide and Rodenticide Act, views the use of PIP corn as positive. Broad spectrum pesticide use has declined since the PIP traits have been introduced. As the agricultural landscape sees a higher percentage of corn acres using the PIP technology, the risk of the targeted insect pest populations developing resistance to the toxins, thereby rendering the in will increase as well. This result would negate the effectiveness of the PIP corn traits and could reduce production of a US field corn crop valued at $33 billion dollars in 2006 and place US food and now energy security at risk. Concerns over insect pest resistance development to PIP traits have led the USEPA to team with NASA and the Institute for Technology Development (ITD) to develop geo-spatial technologies designed to proactively monitor the corn production landscape for insect pest infestation and possible resistance development. USEPA resistance management simulation models are combined with NASA remote sensi ng products to monitor the corn landscape for resistance development. The two agencies have entered into an agreement which could potentially lead to the development of next generation NASA sensors that will more specifically address the requirements of the USEPA's resistance development strategy and offer opportunities to study the ever changing ecosystem complexities. The USEPA/NASA/ITD team has developed a broad research project entitled CERES (Crop Evaluation Research for Environmental Strategies). CERES is a research effort leading to decision support system tools that are designed to integrate multi-resolution NASA remote sensing data products and USEPA geo -spatial models to monitor the potential for insect pest resistance development from the regional to the landscape and then to the field level.

Lower frequency of NPM1 and FLT3-ITD mutations in a South African adult de novo AML cohort

PubMed Central

Marshall, R. C.; Tlagadi, A.; Bronze, M.; Kana, V.; Naidoo, S.; Wiggill, T. M.; Carmona, S. C.

2014-01-01

Introduction Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of haemopoietic progenitor cells diagnosed in individuals of any age, but with a median age of 67 years at presentation in adults. Assessment of the mutation status of Nucleophosmin protein-1 (NPM1) and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) are essential for the diagnosis, prognosis and treatment of AML. Methods A total of 160 de novo AML cases, both cytogenetically normal and abnormal, were analyzed for the presence of NPM1 and FLT3-ITD mutations and the results assessed in conjunction with epidemiological, clinical and laboratory findings. Results NPM1 mutations were found in 7.5%, while FLT3-ITD was present in 12% of these cases. Both of these were lower than expected. The median age at diagnosis of AML was 41 years and for the FLT3-ITD only cases, median age was 33 years; these ages were younger than expected. Conclusion The lower reported frequencies and younger median age at diagnosis of AML and these specific mutations may be contributed to by a number of factors including; effects of race on age of presentation, inclusion of patients diagnosed with de novo AML only and a generally younger median age of the South African population. PMID:24666762

Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition.

PubMed

Gallipoli, Paolo; Giotopoulos, George; Tzelepis, Konstantinos; Costa, Ana S H; Vohra, Shabana; Medina-Perez, Paula; Basheer, Faisal; Marando, Ludovica; Di Lisio, Lorena; Dias, Joao M L; Yun, Haiyang; Sasca, Daniel; Horton, Sarah J; Vassiliou, George; Frezza, Christian; Huntly, Brian J P

2018-04-12

FLT3 internal tandem duplication (FLT3 ITD ) mutations are common in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new-generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3 ITD AML patients remains poor and demands the identification of novel, specific, and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3 ITD AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3 ITD and other TK activating mutation-driven leukemias. © 2018 by The American Society of Hematology.

Optimization of Imidazo[4,5-b]pyridine-Based Kinase Inhibitors: Identification of a Dual FLT3/Aurora Kinase Inhibitor as an Orally Bioavailable Preclinical Development Candidate for the Treatment of Acute Myeloid Leukemia

PubMed Central

2012-01-01

Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A Kd = 7.5 nM, Aurora-B Kd = 48 nM), FLT3 kinase (Kd = 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd = 38 nM) and FLT3(D835Y) (Kd = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20–35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4–11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children. PMID:23043539

Investigations in mechanisms and strategies to enhance hearing with cochlear implants

NASA Astrophysics Data System (ADS)

Churchill, Tyler H.

Cochlear implants (CIs) produce hearing sensations by stimulating the auditory nerve (AN) with current pulses whose amplitudes are modulated by filtered acoustic temporal envelopes. While this technology has provided hearing for multitudinous CI recipients, even bilaterally-implanted listeners have more difficulty understanding speech in noise and localizing sounds than normal hearing (NH) listeners. Three studies reported here have explored ways to improve electric hearing abilities. Vocoders are often used to simulate CIs for NH listeners. Study 1 was a psychoacoustic vocoder study examining the effects of harmonic carrier phase dispersion and simulated CI current spread on speech intelligibility in noise. Results showed that simulated current spread was detrimental to speech understanding and that speech vocoded with carriers whose components' starting phases were equal was the least intelligible. Cross-correlogram analyses of AN model simulations confirmed that carrier component phase dispersion resulted in better neural envelope representation. Localization abilities rely on binaural processing mechanisms in the brainstem and mid-brain that are not fully understood. In Study 2, several potential mechanisms were evaluated based on the ability of metrics extracted from stereo AN simulations to predict azimuthal locations. Results suggest that unique across-frequency patterns of binaural cross-correlation may provide a strong cue set for lateralization and that interaural level differences alone cannot explain NH sensitivity to lateral position. While it is known that many bilateral CI users are sensitive to interaural time differences (ITDs) in low-rate pulsatile stimulation, most contemporary CI processing strategies use high-rate, constant-rate pulse trains. In Study 3, we examined the effects of pulse rate and pulse timing on ITD discrimination, ITD lateralization, and speech recognition by bilateral CI listeners. Results showed that listeners were able to use low-rate pulse timing cues presented redundantly on multiple electrodes for ITD discrimination and lateralization of speech stimuli even when mixed with high rates on other electrodes. These results have contributed to a better understanding of those aspects of the auditory system that support speech understanding and binaural hearing, suggested vocoder parameters that may simulate aspects of electric hearing, and shown that redundant, low-rate pulse timing supports improved spatial hearing for bilateral CI listeners.

Interim Terrain Data (ITD) and Vector Product Interim Terrain Data (VITD) user's guide

DOT National Transportation Integrated Search

1996-09-01

This guide is intended to be a convenient reference for users of these types of terrain analysis data. ITD is a digitized version of the standard 1:50,000-scale tactical terrain analysis data base (TTADB) product produced by the Defense Mapping Agenc...

[Validation of an instrument for screening cases of type 2 diabetes and monitoring at-risk individuals in Mexico].

PubMed

Guerrero-Romero, Fernando; Rodríguez-Morán, Martha

2010-03-01

To validate a method for screening cases of type 2 diabetes and monitoring at-risk people in a community in northern Mexico. The screening instrument for type 2 diabetes (ITD, for its Spanish acronym) was developed using a multiple logistic regression analysis that made it possible to determine the association between a new diagnosis of diabetes (a dependent variable) and 11 known risk factors. Internal validations were performed (through v-fold cross-validation), together with external validations (through the monitoring of a cohort of healthy individuals). In order to estimate the relative risk (RR) of developing type 2 diabetes, the total ITD score is calculated on the basis of an individual's risk factors and compared against a curve that shows the probability of that individual developing the disease. Of the 525 people in the cohort, 438 (83.4%) were followed for an average of 7 years (4.5 to 10 years), for a total of 2 696 person-years; 62 (14.2%) people developed diabetes during the time they were followed. Individuals scoring 55 points based on their risk factors demonstrated a significantly higher risk of developing diabetes in 7 years (RR = 6.1; IC95%: 1.7 to 11.1); the risk was even higher for those with a score of 75 points (RR = 9.4; IC95%: 2.1 to 11.5). The ITD is easy to use and a valid screening alternative for type 2 diabetes. Its use will allow more individuals to benefit from disease prevention methods and early diagnosis without substantially increasing costs and with minimal use of laboratory resources.

Lobed Mixer Optimization for Advanced Ejector Geometries

NASA Technical Reports Server (NTRS)

Waitz, Ian A.

1996-01-01

The overall objectives are: 1) to pursue analytical, computational, and experimental studies that enhance basic understanding of forced mixing phenomena relevant to supersonic jet noise reduction, and 2) to integrate this enhanced understanding (analytical, computational, and empirical) into a design-oriented model of a mixer-ejector noise suppression system. The work is focused on ejector geometries and flow conditions typical of those being investigated in the NASA High Speed Research Program (HSRP). The research will be carried out in collaboration with the NASA HSRP Nozzle Integrated Technology Development (ITD) Team, and will both contribute to, and benefit from, the results of other HSRP research. The noise suppressor system model that is being developed under this grant is distinct from analytical tools developed by industry because it directly links details of lobe geometry to mixer-ejector performance. In addition, the model provides a 'technology road map to define gaps in the current understanding of various phenomena related to mixer-ejector design and to help prioritize research areas. This report describes research completed in the past year, as well as work proposed for the following year.

Reliability of Interaural Time Difference-Based Localization Training in Elderly Individuals with Speech-in-Noise Perception Disorder.

PubMed

Delphi, Maryam; Lotfi, M-Yones; Moossavi, Abdollah; Bakhshi, Enayatollah; Banimostafa, Maryam

2017-09-01

Previous studies have shown that interaural-time-difference (ITD) training can improve localization ability. Surprisingly little is, however, known about localization training vis-à-vis speech perception in noise based on interaural time difference in the envelope (ITD ENV). We sought to investigate the reliability of an ITD ENV-based training program in speech-in-noise perception among elderly individuals with normal hearing and speech-in-noise disorder. The present interventional study was performed during 2016. Sixteen elderly men between 55 and 65 years of age with the clinical diagnosis of normal hearing up to 2000 Hz and speech-in-noise perception disorder participated in this study. The training localization program was based on changes in ITD ENV. In order to evaluate the reliability of the training program, we performed speech-in-noise tests before the training program, immediately afterward, and then at 2 months' follow-up. The reliability of the training program was analyzed using the Friedman test and the SPSS software. Significant statistical differences were shown in the mean scores of speech-in-noise perception between the 3 time points (P=0.001). The results also indicated no difference in the mean scores of speech-in-noise perception between the 2 time points of immediately after the training program and 2 months' follow-up (P=0.212). The present study showed the reliability of an ITD ENV-based localization training in elderly individuals with speech-in-noise perception disorder.

Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML.

PubMed

Sayar, Hamid; Liu, Yan; Gao, Rui; Zaid, Mohammad Abu; Cripe, Larry D; Weisenbach, Jill; Sargent, Katie J; Nassiri, Mehdi; Li, Lang; Konig, Heiko; Suvannasankha, Attaya; Pan, Feng; Shanmugam, Rajasubramaniam; Goswami, Chirayu; Kapur, Reuben; Xu, Mingjiang; Boswell, H Scott

2018-01-19

Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3 , occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3 /Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.

Binaural sensitivity changes between cortical on and off responses

PubMed Central

Dahmen, Johannes C.; King, Andrew J.; Schnupp, Jan W. H.

2011-01-01

Neurons exhibiting on and off responses with different frequency tuning have previously been described in the primary auditory cortex (A1) of anesthetized and awake animals, but it is unknown whether other tuning properties, including sensitivity to binaural localization cues, also differ between on and off responses. We measured the sensitivity of A1 neurons in anesthetized ferrets to 1) interaural level differences (ILDs), using unmodulated broadband noise with varying ILDs and average binaural levels, and 2) interaural time delays (ITDs), using sinusoidally amplitude-modulated broadband noise with varying envelope ITDs. We also assessed fine-structure ITD sensitivity and frequency tuning, using pure-tone stimuli. Neurons most commonly responded to stimulus onset only, but purely off responses and on-off responses were also recorded. Of the units exhibiting significant binaural sensitivity nearly one-quarter showed binaural sensitivity in both on and off responses, but in almost all (∼97%) of these units the binaural tuning of the on responses differed significantly from that seen in the off responses. Moreover, averaged, normalized ILD and ITD tuning curves calculated from all units showing significant sensitivity to binaural cues indicated that on and off responses displayed different sensitivity patterns across the population. A principal component analysis of ITD response functions suggested a continuous cortical distribution of binaural sensitivity, rather than discrete response classes. Rather than reflecting a release from inhibition without any functional significance, we propose that binaural off responses may be important to cortical encoding of sound-source location. PMID:21562191

Crystallographic Texture and Elemental Composition Mapped in Bovine Root Dentin at the 200 nm Level

PubMed Central

Deymier-Black, A. C.; Veis, A.; Cai, Z.; Stock, S. R.

2015-01-01

Summary The relationship between the mineralization of peritubular dentin (PTD) and intertubular dentin (ITD) is not well understood. Tubules are quite small, diameter ~2 μm, and this makes the near-tubule region of dentin difficult to study. Here, advanced characterization techniques are applied in a novel way to examine what organic or nanostructural signatures may indicate the end of ITD or the beginning of PTD mineralization. X-ray fluorescence intensity (Ca, P, and Zn) and X-ray diffraction patterns from carbonated apatite (cAp) were mapped around dentintubules at resolutions ten times smaller than the feature size (200 nm pixels), representing a 36% increase in resolution over earlier work. In the near tubule volumes of near-pulp, root dentin, Zn intensity was higher than in ITD remote from the tubules. This increase in Zn2+, as determined by X-ray absorption near edge structure analysis, may indicate the presence of metalloenzymes or transcription factors important to ITD or PTD mineralization. The profiles of the cAp 00.2 X-ray diffraction rings were fitted with a pseudo-Voigt function, and the spatial and azimuthal distribution of these rings’ integrated intensities indicated that the cAp platelets were arranged with their c-axes aligned tangential to the edge of the tubule lumen. This texture was continuous throughout the dentin indicating a lack of structural difference between in the Zn rich near-tubular region and the remote ITD. PMID:23630059

The representation of sound localization cues in the barn owl's inferior colliculus

PubMed Central

Singheiser, Martin; Gutfreund, Yoram; Wagner, Hermann

2012-01-01

The barn owl is a well-known model system for studying auditory processing and sound localization. This article reviews the morphological and functional organization, as well as the role of the underlying microcircuits, of the barn owl's inferior colliculus (IC). We focus on the processing of frequency and interaural time (ITD) and level differences (ILD). We first summarize the morphology of the sub-nuclei belonging to the IC and their differentiation by antero- and retrograde labeling and by staining with various antibodies. We then focus on the response properties of neurons in the three major sub-nuclei of IC [core of the central nucleus of the IC (ICCc), lateral shell of the central nucleus of the IC (ICCls), and the external nucleus of the IC (ICX)]. ICCc projects to ICCls, which in turn sends its information to ICX. The responses of neurons in ICCc are sensitive to changes in ITD but not to changes in ILD. The distribution of ITD sensitivity with frequency in ICCc can only partly be explained by optimal coding. We continue with the tuning properties of ICCls neurons, the first station in the midbrain where the ITD and ILD pathways merge after they have split at the level of the cochlear nucleus. The ICCc and ICCls share similar ITD and frequency tuning. By contrast, ICCls shows sigmoidal ILD tuning which is absent in ICCc. Both ICCc and ICCls project to the forebrain, and ICCls also projects to ICX, where space-specific neurons are found. Space-specific neurons exhibit side peak suppression in ITD tuning, bell-shaped ILD tuning, and are broadly tuned to frequency. These neurons respond only to restricted positions of auditory space and form a map of two-dimensional auditory space. Finally, we briefly review major IC features, including multiplication-like computations, correlates of echo suppression, plasticity, and adaptation. PMID:22798945

Neural coding of time-varying interaural time differences and time-varying amplitude in the inferior colliculus

PubMed Central

2017-01-01

Binaural cues occurring in natural environments are frequently time varying, either from the motion of a sound source or through interactions between the cues produced by multiple sources. Yet, a broad understanding of how the auditory system processes dynamic binaural cues is still lacking. In the current study, we directly compared neural responses in the inferior colliculus (IC) of unanesthetized rabbits to broadband noise with time-varying interaural time differences (ITD) with responses to noise with sinusoidal amplitude modulation (SAM) over a wide range of modulation frequencies. On the basis of prior research, we hypothesized that the IC, one of the first stages to exhibit tuning of firing rate to modulation frequency, might use a common mechanism to encode time-varying information in general. Instead, we found weaker temporal coding for dynamic ITD compared with amplitude modulation and stronger effects of adaptation for amplitude modulation. The differences in temporal coding of dynamic ITD compared with SAM at the single-neuron level could be a neural correlate of “binaural sluggishness,” the inability to perceive fluctuations in time-varying binaural cues at high modulation frequencies, for which a physiological explanation has so far remained elusive. At ITD-variation frequencies of 64 Hz and above, where a temporal code was less effective, noise with a dynamic ITD could still be distinguished from noise with a constant ITD through differences in average firing rate in many neurons, suggesting a frequency-dependent tradeoff between rate and temporal coding of time-varying binaural information. NEW & NOTEWORTHY Humans use time-varying binaural cues to parse auditory scenes comprising multiple sound sources and reverberation. However, the neural mechanisms for doing so are poorly understood. Our results demonstrate a potential neural correlate for the reduced detectability of fluctuations in time-varying binaural information at high speeds, as occurs in reverberation. The results also suggest that the neural mechanisms for processing time-varying binaural and monaural cues are largely distinct. PMID:28381487

The effects of experimentally induced conductive hearing loss on spectral and temporal aspects of sound transmission through the ear.

PubMed

Eric Lupo, J; Koka, Kanthaiah; Thornton, Jennifer L; Tollin, Daniel J

2011-02-01

Conductive hearing loss (CHL) is known to produce hearing deficits, including deficits in sound localization ability. The differences in sound intensities and timing experienced between the two tympanic membranes are important cues to sound localization (ILD and ITD, respectively). Although much is known about the effect of CHL on hearing levels, little investigation has been conducted into the actual impact of CHL on sound location cues. This study investigated effects of CHL induced by earplugs on cochlear microphonic (CM) amplitude and timing and their corresponding effect on the ILD and ITD location cues. Acoustic and CM measurements were made in 5 chinchillas before and after earplug insertion, and again after earplug removal using pure tones (500 Hz to 24 kHz). ILDs in the unoccluded condition demonstrated position and frequency dependence where peak far-lateral ILDs approached 30 dB for high frequencies. Unoccluded ear ITD cues demonstrated positional and frequency dependence with increased ITD cue for both decreasing frequency (±420 μs at 500 Hz, ±310 μs for 1-4 kHz) and increasingly lateral sound source locations. Occlusion of the ear canal with foam plugs resulted in a mild, frequency-dependent conductive hearing loss of 10-38 dB (mean 31 ± 3.9 dB) leading to a concomitant frequency dependent increase in ILDs at all source locations. The effective ITDs increased in a frequency dependent manner with ear occlusion as a direct result of the acoustic properties of the plugging material, the latter confirmed via acoustical measurements using a model ear canal with varying volumes of acoustic foam. Upon ear plugging with acoustic foam, a mild CHL is induced. Furthermore, the CHL induced by acoustic foam results in substantial changes in the magnitudes of both the ITD and ILD cues to sound location. Copyright © 2010 Elsevier B.V. All rights reserved.

The effects of experimentally induced conductive hearing loss on spectral and temporal aspects of sound transmission through the ear

PubMed Central

Lupo, J. Eric; Koka, Kanthaiah; Thornton, Jennifer L.; Tollin, Daniel J.

2010-01-01

Conductive hearing loss (CHL) is known to produce hearing deficits, including deficits in sound localization ability. The differences in sound intensities and timing experienced between the two tympanic membranes are important cues to sound localization (ILD and ITD, respectively). Although much is known about the effect of CHL on hearing levels, little investigation has been conducted into the actual impact of CHL on sound location cues. This study investigated effects of CHL induced by earplugs on cochlear microphonic (CM) amplitude and timing and their corresponding effect on the ILD and ITD location cues. Acoustic and CM measurements were made in 5 chinchillas before and after earplug insertion, and again after earplug removal using pure tones (500 Hz to 24 kHz). ILDs in the unoccluded condition demonstrated position and frequency dependence where peak far-lateral ILDs approached 30 dB for high frequencies. Unoccluded ear ITD cues demonstrated positional and frequency dependence with increased ITD cue for both decreasing frequency (± 420 µs at 500 Hz, ± 310 µs for 1–4 kHz ) and increasingly lateral sound source locations. Occlusion of the ear canal with foam plugs resulted in a mild, frequency-dependent conductive hearing loss of 10–38 dB (mean 31 ± 3.9 dB) leading to a concomitant frequency dependent increase in ILDs at all source locations. The effective ITDs increased in a frequency dependent manner with ear occlusion as a direct result of the acoustic properties of the plugging material, the latter confirmed via acoustical measurements using a model ear canal with varying volumes of acoustic foam. Upon ear plugging with acoustic foam, a mild CHL is induced. Furthermore, the CHL induced by acoustic foam results in substantial changes in the magnitudes of both the ITD and ILD cues to sound location. PMID:21073935

Spatial selectivity and binaural responses in the inferior colliculus of the great horned owl.

PubMed

Volman, S F; Konishi, M

1989-09-01

In this study we have investigated the processing of auditory cues for sound localization in the great horned owl (Bubo virginianus). Previous studies have shown that the barn owl, whose ears are asymmetrically oriented in the vertical plane, has a 2-dimensional, topographic representation of auditory space in the external division of the inferior colliculus (ICx). As in the barn owl, the great horned owl's ICx is anatomically distinct and projects to the optic tectum. Neurons in ICx respond over only a small range of azimuths (mean = 32 degrees), and azimuth is topographically mapped. In contrast to the barn owl, the great horned owl has bilaterally symmetrical ears and its receptive fields are not restricted in elevation. The binaural cues available for sound localization were measured both with cochlear microphonic recordings and with a microphone attached to a probe tube in the auditory canal. Interaural time disparity (ITD) varied monotonically with azimuth. Interaural intensity differences (IID) also changed with azimuth, but the largest IIDs were less than 15 dB, and the variation was not monotonic. Neither ITD nor IID varied systematically with changes in the vertical position of a sound source. We used dichotic stimulation to determine the sensitivity of ICx neurons to these binaural cues. Best ITD of ICx units was topographically mapped and strongly correlated with receptive-field azimuth. The width of ITD tuning curves, measured at 50% of the maximum response, averaged 72 microseconds. All ICx neurons responded only to binaural stimulation and had nonmonotonic IID tuning curves. Best IID was weakly, but significantly, correlated with best ITD (r = 0.39, p less than 0.05). The IID tuning curves, however, were broad (mean 50% width = 24 dB), and 67% of the units had best IIDs within 5 dB of 0 dB IID. ITD tuning was sensitive to variations in IID in the direction opposite to that expected for time-intensity trading, but the magnitude of this effect was only 1.5 microseconds/dB IID. We conclude that, in the great horned owl, the spatial selectivity of ICx neurons arises primarily from their ITD tuning. Except for the absence of elevation selectivity and the narrow range of best IIDs, ICx in the great horned owl appears to be organized much the same as in the barn owl.

SPECT System Optimization Against A Discrete Parameter Space

PubMed Central

Meng, L. J.; Li, N.

2013-01-01

In this paper, we present an analytical approach for optimizing the design of a static SPECT system or optimizing the sampling strategy with a variable/adaptive SPECT imaging hardware against an arbitrarily given set of system parameters. This approach has three key aspects. First, it is designed to operate over a discretized system parameter space. Second, we have introduced an artificial concept of virtual detector as the basic building block of an imaging system. With a SPECT system described as a collection of the virtual detectors, one can convert the task of system optimization into a process of finding the optimum imaging time distribution (ITD) across all virtual detectors. Thirdly, the optimization problem (finding the optimum ITD) could be solved with a block-iterative approach or other non-linear optimization algorithms. In essence, the resultant optimum ITD could provide a quantitative measure of the relative importance (or effectiveness) of the virtual detectors and help to identify the system configuration or sampling strategy that leads to an optimum imaging performance. Although we are using SPECT imaging as a platform to demonstrate the system optimization strategy, this development also provides a useful framework for system optimization problems in other modalities, such as positron emission tomography (PET) and X-ray computed tomography (CT) [1, 2]. PMID:23587609

PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy.

PubMed

Cicconi, L; Divona, M; Ciardi, C; Ottone, T; Ferrantini, A; Lavorgna, S; Alfonso, V; Paoloni, F; Piciocchi, A; Avvisati, G; Ferrara, F; Di Bona, E; Albano, F; Breccia, M; Cerqui, E; Sborgia, M; Kropp, M G; Santoro, A; Levis, A; Sica, S; Amadori, S; Voso, M T; Mandelli, F; Lo-Coco, F

2016-10-01

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

Predicting binaural responses from monaural responses in the gerbil medial superior olive

PubMed Central

Plauška, Andrius; Borst, J. Gerard

2016-01-01

Accurate sound source localization of low-frequency sounds in the horizontal plane depends critically on the comparison of arrival times at both ears. A specialized brainstem circuit containing the principal neurons of the medial superior olive (MSO) is dedicated to this comparison. MSO neurons are innervated by segregated inputs from both ears. The coincident arrival of excitatory inputs from both ears is thought to trigger action potentials, with differences in internal delays creating a unique sensitivity to interaural time differences (ITDs) for each cell. How the inputs from both ears are integrated by the MSO neurons is still debated. Using juxtacellular recordings, we tested to what extent MSO neurons from anesthetized Mongolian gerbils function as simple cross-correlators of their bilateral inputs. From the measured subthreshold responses to monaural wideband stimuli we predicted the rate-ITD functions obtained from the same MSO neuron, which have a damped oscillatory shape. The rate of the oscillations and the position of the peaks and troughs were accurately predicted. The amplitude ratio between dominant and secondary peaks of the rate-ITD function, captured in the width of its envelope, was not always exactly reproduced. This minor imperfection pointed to the methodological limitation of using a linear representation of the monaural inputs, which disregards any temporal sharpening occurring in the cochlear nucleus. The successful prediction of the major aspects of rate-ITD curves supports a simple scheme in which the ITD sensitivity of MSO neurons is realized by the coincidence detection of excitatory monaural inputs. PMID:27009164

Axonal recordings from medial superior olive neurons obtained from the lateral lemniscus of the chinchilla (Chinchilla laniger).

PubMed

Bremen, Peter; Joris, Philip X

2013-10-30

Interaural time differences (ITDs) are a major cue for localizing low-frequency (<1.5 kHz) sounds. Sensitivity to this cue first occurs in the medial superior olive (MSO), which is thought to perform a coincidence analysis on its monaural inputs. Extracellular single-neuron recordings in MSO are difficult to obtain because (1) MSO action potentials are small and (2) a large field potential locked to the stimulus waveform hampers spike isolation. Consequently, only a limited number of studies report MSO data, and even in these studies data are limited in the variety of stimuli used, in the number of neurons studied, and in spike isolation. More high-quality data are needed to better understand the mechanisms underlying neuronal ITD-sensitivity. We circumvented these difficulties by recording from the axons of MSO neurons in the lateral lemniscus (LL) of the chinchilla, a species with pronounced low-frequency sensitivity. Employing sharp glass electrodes we successfully recorded from neurons with ITD sensitivity: the location, response properties, latency, and spike shape were consistent with an MSO axonal origin. The main difficulty encountered was mechanical stability. We obtained responses to binaural beats and dichotic noise bursts to characterize the best delay versus characteristic frequency distribution, and compared the data to recordings we obtained in the inferior colliculus (IC). In contrast to most reports in other rodents, many best delays were close to zero ITD, both in MSO and IC, with a majority of the neurons recorded in the LL firing maximally within the presumed ethological ITD range.

Updating a Strategic Highway Safety Plan : Learning from the Idaho Transportation Department (ITD) - Proceedings from the Federal Highway Administration's (FHWA) Highway Safety Peer-to-Peer Exchange Program

DOT National Transportation Integrated Search

2009-10-01

On November 4, 2009, ITDs Office of Highway Operations and Safety partnered with the FHWA Office of Safety to host a one-day peer exchange. This event focused on the update of Idahos Strategic Highway Safety Plan (SHSP), entitled Toward Zero...

Lateralization of high-frequency transposed stimuli under conditions of binaural interference

NASA Astrophysics Data System (ADS)

Bernstein, Leslie R.; Trahiotis, Constantine

2005-04-01

The purpose of this study was to determine whether binaural interference would occur if ITD-based extents of laterality were measured using high-frequency transposed stimuli as targets. The results of an earlier study [L. R. Bernstein and C. Trahiotis, J. Acoust. Soc. Am. 116, 3062-3069 (2004)], which focused on threshold-ITDs rather than extents of laterality, suggested that high-frequency transposed stimuli might be immune to binaural interference effects resulting from the addition of a spectrally-remote, low-frequency interferer. In contrast to the earlier findings, the data from this study indicate that high-frequency transposed targets can, indeed, be susceptible to binaural interference. High-frequency transposed targets, even when presented along with an interferer, yielded greater extents of ITD-based laterality than did Gaussian noise targets presented in isolation. That is, the enhanced potency of ITDs conveyed by transposed stimuli persisted even in the presence of a low-frequency interferer. Predictions made using an extension of the model of Heller and Trahiotis [L. M. Heller and C. Trahiotis, J. Acoust. Soc. Am. 99, 3632-3637 (1996)] accounted well for binaural interference obtained with conventional Gaussian noise targets but generally over-predicted the amounts of interference found with the transposed targets.

Spatial hearing benefits demonstrated with presentation of acoustic temporal fine structure cues in bilateral cochlear implant listeners.

PubMed

Churchill, Tyler H; Kan, Alan; Goupell, Matthew J; Litovsky, Ruth Y

2014-09-01

Most contemporary cochlear implant (CI) processing strategies discard acoustic temporal fine structure (TFS) information, and this may contribute to the observed deficits in bilateral CI listeners' ability to localize sounds when compared to normal hearing listeners. Additionally, for best speech envelope representation, most contemporary speech processing strategies use high-rate carriers (≥900 Hz) that exceed the limit for interaural pulse timing to provide useful binaural information. Many bilateral CI listeners are sensitive to interaural time differences (ITDs) in low-rate (<300 Hz) constant-amplitude pulse trains. This study explored the trade-off between superior speech temporal envelope representation with high-rate carriers and binaural pulse timing sensitivity with low-rate carriers. The effects of carrier pulse rate and pulse timing on ITD discrimination, ITD lateralization, and speech recognition in quiet were examined in eight bilateral CI listeners. Stimuli consisted of speech tokens processed at different electrical stimulation rates, and pulse timings that either preserved or did not preserve acoustic TFS cues. Results showed that CI listeners were able to use low-rate pulse timing cues derived from acoustic TFS when presented redundantly on multiple electrodes for ITD discrimination and lateralization of speech stimuli.

Spectrotemporal weighting of binaural cues: Effects of a diotic interferer on discrimination of dynamic interaural differences

PubMed Central

Bibee, Jacqueline M.; Stecker, G. Christopher

2016-01-01

Spatial judgments are often dominated by low-frequency binaural cues and onset cues when binaural cues vary across the spectrum and duration, respectively, of a brief sound. This study combined these dimensions to assess the spectrotemporal weighting of binaural information. Listeners discriminated target interaural time difference (ITD) and interaural level difference (ILD) carried by the onset, offset, or full duration of a 4-kHz Gabor click train with a 2-ms period in the presence or absence of a diotic 500-Hz interferer tone. ITD and ILD thresholds were significantly elevated by the interferer in all conditions and by a similar amount to previous reports for static cues. Binaural interference was dramatically greater for ITD targets lacking onset cues compared to onset and full-duration conditions. Binaural interference for ILD targets was similar across dynamic-cue conditions. These effects mirror the baseline discriminability of dynamic ITD and ILD cues [Stecker and Brown. (2010). J. Acoust. Soc. Am. 127, 3092–3103], consistent with stronger interference for less-robust/higher-variance cues. The results support the view that binaural cue integration occurs simultaneously across multiple variance-weighted dimensions, including time and frequency. PMID:27794286

Spectrotemporal weighting of binaural cues: Effects of a diotic interferer on discrimination of dynamic interaural differences.

PubMed

Bibee, Jacqueline M; Stecker, G Christopher

2016-10-01

Spatial judgments are often dominated by low-frequency binaural cues and onset cues when binaural cues vary across the spectrum and duration, respectively, of a brief sound. This study combined these dimensions to assess the spectrotemporal weighting of binaural information. Listeners discriminated target interaural time difference (ITD) and interaural level difference (ILD) carried by the onset, offset, or full duration of a 4-kHz Gabor click train with a 2-ms period in the presence or absence of a diotic 500-Hz interferer tone. ITD and ILD thresholds were significantly elevated by the interferer in all conditions and by a similar amount to previous reports for static cues. Binaural interference was dramatically greater for ITD targets lacking onset cues compared to onset and full-duration conditions. Binaural interference for ILD targets was similar across dynamic-cue conditions. These effects mirror the baseline discriminability of dynamic ITD and ILD cues [Stecker and Brown. (2010). J. Acoust. Soc. Am. 127, 3092-3103], consistent with stronger interference for less-robust/higher-variance cues. The results support the view that binaural cue integration occurs simultaneously across multiple variance-weighted dimensions, including time and frequency.

Sensitivity to envelope-based interaural delays at high frequencies: center frequency affects the envelope rate-limitation.

PubMed

Bernstein, Leslie R; Trahiotis, Constantine

2014-02-01

Sensitivity to ongoing interaural temporal disparities (ITDs) was measured using bandpass-filtered pulse trains centered at 4600, 6500, or 9200 Hz. Save for minor differences in the exact center frequencies, those target stimuli were those employed by Majdak and Laback [J. Acoust. Soc. Am. 125, 3903-3913 (2009)]. At each center frequency, threshold ITD was measured for pulse repetition rates ranging from 64 to 609 Hz. The results and quantitative predictions by a cross-correlation-based model indicated that (1) at most pulse repetition rates, threshold ITD increased with center frequency, (2) the cutoff frequency of the putative envelope low-pass filter that determines sensitivity to ITD at high envelope rates appears to be inversely related to center frequency, and (3) both outcomes were accounted for by assuming that, independent of the center frequency, the listeners' decision variable was a constant criterion change in interaural correlation of the stimuli as processed internally. The finding of an inverse relation between center frequency and the envelope rate limitation, while consistent with much prior literature, runs counter to the conclusion reached by Majdak and Laback.

78 FR 59008 - Grant of Interim Extension of the Term of U.S. Patent No. 5,454,779; ResQPump®/ResQPOD® ITD

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-25

... of the application indicates that, except for permission to market or use the product commercially... University of California timely filed an application under 35 U.S.C. 156(d)(5) for a second interim extension... connection with the ResQPOD[supreg] ITD. The application indicates that a Premarket Approval Application, PMA...

Ground test for vibration control demonstrator

NASA Astrophysics Data System (ADS)

Meyer, C.; Prodigue, J.; Broux, G.; Cantinaud, O.; Poussot-Vassal, C.

2016-09-01

In the objective of maximizing comfort in Falcon jets, Dassault Aviation is developing an innovative vibration control technology. Vibrations of the structure are measured at several locations and sent to a dedicated high performance vibration control computer. Control laws are implemented in this computer to analyse the vibrations in real time, and then elaborate orders sent to the existing control surfaces to counteract vibrations. After detailing the technology principles, this paper focuses on the vibration control ground demonstration that was performed by Dassault Aviation in May 2015 on Falcon 7X business jet. The goal of this test was to attenuate vibrations resulting from fixed forced excitation delivered by shakers. The ground test demonstrated the capability to implement an efficient closed-loop vibration control with a significant vibration level reduction and validated the vibration control law design methodology. This successful ground test was a prerequisite before the flight test demonstration that is now being prepared. This study has been partly supported by the JTI CleanSky SFWA-ITD.

The acoustical cues to sound location in the Guinea pig (cavia porcellus)

PubMed Central

Greene, Nathanial T; Anbuhl, Kelsey L; Williams, Whitney; Tollin, Daniel J.

2014-01-01

There are three main acoustical cues to sound location, each attributable to space-and frequency-dependent filtering of the propagating sound waves by the outer ears, head, and torso: Interaural differences in time (ITD) and level (ILD) as well as monaural spectral shape cues. While the guinea pig has been a common model for studying the anatomy, physiology, and behavior of binaural and spatial hearing, extensive measurements of their available acoustical cues are lacking. Here, these cues were determined from directional transfer functions (DTFs), the directional components of the head-related transfer functions, for eleven adult guinea pigs. In the frontal hemisphere, monaural spectral notches were present for frequencies from ~10 to 20 kHz; in general, the notch frequency increased with increasing sound source elevation and in azimuth toward the contralateral ear. The maximum ITDs calculated from low-pass filtered (2 kHz cutoff frequency) DTFs were ~250 µs, whereas the maximum ITD measured with low frequency tone pips was over 320 µs. A spherical head model underestimates ITD magnitude under normal conditions, but closely approximates values when the pinnae were removed. Interaural level differences (ILDs) strongly depended on location and frequency; maximum ILDs were < 10 dB for frequencies < 4 kHz and were as large as 40 dB for frequencies > 10 kHz. Removal of the pinna reduced the depth and sharpness of spectral notches, altered the acoustical axis, and reduced the acoustical gain, ITDs, and ILDs; however, spectral shape features and acoustical gain were not completely eliminated, suggesting a substantial contribution of the head and torso in altering the sounds present at the tympanic membrane. PMID:25051197

Time-Varying Distortions of Binaural Information by Bilateral Hearing Aids: Effects of Nonlinear Frequency Compression.

PubMed

Brown, Andrew D; Rodriguez, Francisco A; Portnuff, Cory D F; Goupell, Matthew J; Tollin, Daniel J

2016-10-03

In patients with bilateral hearing loss, the use of two hearing aids (HAs) offers the potential to restore the benefits of binaural hearing, including sound source localization and segregation. However, existing evidence suggests that bilateral HA users' access to binaural information, namely interaural time and level differences (ITDs and ILDs), can be compromised by device processing. Our objective was to characterize the nature and magnitude of binaural distortions caused by modern digital behind-the-ear HAs using a variety of stimuli and HA program settings. Of particular interest was a common frequency-lowering algorithm known as nonlinear frequency compression, which has not previously been assessed for its effects on binaural information. A binaural beamforming algorithm was also assessed. Wide dynamic range compression was enabled in all programs. HAs were placed on a binaural manikin, and stimuli were presented from an arc of loudspeakers inside an anechoic chamber. Stimuli were broadband noise bursts, 10-Hz sinusoidally amplitude-modulated noise bursts, or consonant-vowel-consonant speech tokens. Binaural information was analyzed in terms of ITDs, ILDs, and interaural coherence, both for whole stimuli and in a time-varying sense (i.e., within a running temporal window) across four different frequency bands (1, 2, 4, and 6 kHz). Key findings were: (a) Nonlinear frequency compression caused distortions of high-frequency envelope ITDs and significantly reduced interaural coherence. (b) For modulated stimuli, all programs caused time-varying distortion of ILDs. (c) HAs altered the relationship between ITDs and ILDs, introducing large ITD-ILD conflicts in some cases. Potential perceptual consequences of measured distortions are discussed. © The Author(s) 2016.

Tonotopic tuning in a sound localization circuit.

PubMed

Slee, Sean J; Higgs, Matthew H; Fairhall, Adrienne L; Spain, William J

2010-05-01

Nucleus laminaris (NL) neurons encode interaural time difference (ITD), the cue used to localize low-frequency sounds. A physiologically based model of NL input suggests that ITD information is contained in narrow frequency bands around harmonics of the sound frequency. This suggested a theory, which predicts that, for each tone frequency, there is an optimal time course for synaptic inputs to NL that will elicit the largest modulation of NL firing rate as a function of ITD. The theory also suggested that neurons in different tonotopic regions of NL require specialized tuning to take advantage of the input gradient. Tonotopic tuning in NL was investigated in brain slices by separating the nucleus into three regions based on its anatomical tonotopic map. Patch-clamp recordings in each region were used to measure both the synaptic and the intrinsic electrical properties. The data revealed a tonotopic gradient of synaptic time course that closely matched the theoretical predictions. We also found postsynaptic band-pass filtering. Analysis of the combined synaptic and postsynaptic filters revealed a frequency-dependent gradient of gain for the transformation of tone amplitude to NL firing rate modulation. Models constructed from the experimental data for each tonotopic region demonstrate that the tonotopic tuning measured in NL can improve ITD encoding across sound frequencies.

Measures of extents of laterality for high-frequency ``transposed'' stimuli under conditions of binaural interference

NASA Astrophysics Data System (ADS)

Bernstein, Leslie R.; Trahiotis, Constantine

2005-09-01

Our purpose in this study was to determine whether across-frequency binaural interference would occur if ITD-based extents of laterality were measured using high-frequency transposed stimuli as targets. The results of an earlier study [L. R. Bernstein and C. Trahiotis, J. Acoust. Soc. Am. 116, 3062-3069 (2004)], which focused on threshold-ITDs, rather than extents of laterality, suggested that high-frequency transposed stimuli might be ``immune'' to binaural interference effects resulting from the addition of a spectrally remote, low-frequency interferer. In contrast to the earlier findings, the data from this study indicate that high-frequency transposed targets are susceptible to binaural interference. Nevertheless, high-frequency transposed targets, even when presented along with an interferer, yielded greater extents of ITD-based laterality than did high-frequency Gaussian noise targets presented in isolation. That is, the ``enhanced potency'' of ITDs conveyed by transposed stimuli persisted, even in the presence of a low-frequency interferer. Predictions made using an extension of the model of Heller and Trahiotis [L. M. Heller and C. Trahiotis, J. Acoust. Soc. Am. 99, 3632-3637 (1996)] accounted well for across-frequency binaural interference obtained with conventional Gaussian noise targets but, in all but one case, overpredicted the amounts of interference found with the transposed targets.

The favorable impact of CEBPA mutations in patients with acute myeloid leukemia is only observed in the absence of associated cytogenetic abnormalities and FLT3 internal duplication.

PubMed

Renneville, Aline; Boissel, Nicolas; Gachard, Nathalie; Naguib, Dina; Bastard, Christian; de Botton, Stéphane; Nibourel, Olivier; Pautas, Cécile; Reman, Oumedaly; Thomas, Xavier; Gardin, Claude; Terré, Christine; Castaigne, Sylvie; Preudhomme, Claude; Dombret, Hervé

2009-05-21

Mutations of the CCAAT/enhancer binding protein alpha (CEBPA) gene have been associated with a favorable outcome in patients with acute myeloid leukemia (AML), but mainly in those with a normal karyotype. Here, we analyzed the impact of associated cytogenetic abnormalities or bad-prognosis fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in 53 patients with CEBPA(+) de novo AML treated in the Acute Leukemia French Association trials. We found that only those with a normal karyotype and no FLT3-ITD displayed the expected favorable outcome. In this context, relapse-free, disease-free, and overall survival were significantly longer than in corresponding patients without the CEBPA mutation (P = .035, .016, and .047, respectively). This was not observed in the context of an abnormal karyotype or associated FLT3-ITD. Furthermore, after adjustment on age, trial, and mutation type, these features were independently predictive of shorter overall survival in the subset of patients with CEBPA(+) AML (multivariate hazard ratio = 2.7; 95% confidence interval, 1.08-6.7; and 2.9; 95% confidence interval, 1.01-8.2; with P = .034 and .05, for abnormal karyotype and FLT3-ITD, respectively).

Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.

PubMed

Cortes, Jorge; Perl, Alexander E; Döhner, Hartmut; Kantarjian, Hagop; Martinelli, Giovanni; Kovacsovics, Tibor; Rousselot, Philippe; Steffen, Björn; Dombret, Hervé; Estey, Elihu; Strickland, Stephen; Altman, Jessica K; Baldus, Claudia D; Burnett, Alan; Krämer, Alwin; Russell, Nigel; Shah, Neil P; Smith, Catherine C; Wang, Eunice S; Ifrah, Norbert; Gammon, Guy; Trone, Denise; Lazzaretto, Deborah; Levis, Mark

2018-05-30

Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia. We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2. Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses. Ambit Biosciences/Daiichi Sankyo. Copyright © 2018 Elsevier Ltd. All rights reserved.

Glycinergic inhibition tunes coincidence detection in the auditory brainstem

PubMed Central

Myoga, Michael H.; Lehnert, Simon; Leibold, Christian; Felmy, Felix; Grothe, Benedikt

2014-01-01

Neurons in the medial superior olive (MSO) detect microsecond differences in the arrival time of sounds between the ears (interaural time differences or ITDs), a crucial binaural cue for sound localization. Synaptic inhibition has been implicated in tuning ITD sensitivity, but the cellular mechanisms underlying its influence on coincidence detection are debated. Here we determine the impact of inhibition on coincidence detection in adult Mongolian gerbil MSO brain slices by testing precise temporal integration of measured synaptic responses using conductance-clamp. We find that inhibition dynamically shifts the peak timing of excitation, depending on its relative arrival time, which in turn modulates the timing of best coincidence detection. Inhibitory control of coincidence detection timing is consistent with the diversity of ITD functions observed in vivo and is robust under physiologically relevant conditions. Our results provide strong evidence that temporal interactions between excitation and inhibition on microsecond timescales are critical for binaural processing. PMID:24804642

JNDS of interaural time delay (ITD) of selected frequency bands in speech and music signals

NASA Astrophysics Data System (ADS)

Aliphas, Avner; Colburn, H. Steven; Ghitza, Oded

2002-05-01

JNDS of interaural time delay (ITD) of selected frequency bands in the presence of other frequency bands have been reported for noiseband stimuli [Zurek (1985); Trahiotis and Bernstein (1990)]. Similar measurements will be reported for speech and music signals. When stimuli are synthesized with bandpass/band-stop operations, performance with complex stimuli are similar to noisebands (JNDS in tens or hundreds of microseconds); however, the resulting waveforms, when viewed through a model of the auditory periphery, show distortions (irregularities in phase and level) at the boundaries of the target band of frequencies. An alternate synthesis method based upon group-delay filtering operations does not show these distortions and is being used for the current measurements. Preliminary measurements indicate that when music stimuli are created using the new techniques, JNDS of ITDs are increased significantly compared to previous studies, with values on the order of milliseconds.

Multispectral diagnostic imaging of the iris in pigment dispersion syndrome.

PubMed

Roberts, Daniel K; Lukic, Ana; Yang, Yongyi; Wilensky, Jacob T; Wernick, Miles N

2012-08-01

To determine if wavelength selection with near infrared iris imaging may enhance iris transillumination defects (ITDs) in pigment dispersion syndrome. An experimental apparatus was used to acquire iris images in 6 African-American (AA) and 6 White patients with pigment dispersion syndrome. Light-emitting diode probes of 6 different spectral bands (700 to 950 nm) were used to project light into patients' eyes. Iris patterns were photographed, ITD regions of interest were outlined, and region of interest contrasts were calculated for each spectral band. Contrasts varied as a function of wavelength (P<0.0001) for both groups, but tended to be highest in the 700 to 800 nm range. Contrasts were higher in Whites than AAs at 700 nm but the opposite was found at 810 nm (P<0.001). Optimized near infrared iris imaging may be wavelength dependent. Ideal wavelength to image ITDs in more pigmented eyes may be slightly longer than for less pigmented eyes.

FLT3-ITD and MLL-PTD influence the expression of MDR-1, MRP-1, and BCRP mRNA but not LRP mRNA assessed with RQ-PCR method in adult acute myeloid leukemia.

PubMed

Nasilowska-Adamska, Barbara; Solarska, Iwona; Paluszewska, Monika; Malinowska, Iwona; Jedrzejczak, Wieslaw W; Warzocha, Krzysztof

2014-04-01

Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and mixed-lineage leukemia gene-partial tandem duplication (MLL-PTD) are aberrations associated with leukemia which indicate unsatisfactory prognosis. Downstream regulatory targets of FLT3-ITD and MLL-PTD are not well defined. We have analyzed the expression of MDR-1, multidrug resistant protein-1 (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) messenger RNA (mRNA) in relation to the mutational status of FLT3-ITD and MLL-PTD in 185 acute myeloid leukemia (AML) adult patients. The real-time quantitative polymerase chain reaction method was performed to assess the expression of the MDR-1, MRP-1, BCRP, and LRP mRNA, and the results were presented as coefficients calculated using an intermediate method according to Pfaffl's rule. Significantly higher expressions of MDR-1 mRNA were found in patients who did not harbor FLT3-ITD (0.20 vs. 0.05; p = 0.0001) and MRP-1 mRNA in patients with this mutation (0.96 vs. 0.70; p = 0.002) and of BCRP mRNA in patients with MLL-PTD (0.61 vs. 0.38; p = 0.03). In univariate analysis, the high expression of MDR-1 mRNA (≥0.1317) negatively influenced the outcome of induction therapy (p = 0.05), whereas the high expression of BCRP mRNA (≥1.1487) was associated with a high relapse rate (RR) (p = 0.013). We found that the high expression of MDR-1 (≥0.1317), MRP-1 (≥0.8409), and BCRP mRNA (≥1.1487) significantly influenced disease-free survival (DFS; p = 0.059, 0.032, and 0.009, respectively) and overall survival (0.048, 0.014, and 0.059, respectively). Moreover, a high expression of BCRP mRNA (≥1.1487) proved to be an independent prognostic factor for RR (p = 0.01) and DFS (p = 0.002) in multivariate analysis. The significant correlation between the expression of MDR-1, MRP-1, and BCRP mRNA and FLT3-ITD or MLL-PTD in AML patients requires further investigation.

Enhancing Communication in Noisy Environments

DTIC Science & Technology

2009-10-01

derived from the ITD and ILD cues, which are binaural . ITD depends on the azimuthal position of the source. Similarly, ILD refers to the fact...4.4 dB No Perceptual Binaural Speech Enhancement [42] 4.5 dB Yes Fuzzy Cocktail Party Processor [25] 7.5 dB Yes Binaural segregation [43] 8.9 dB No...modulation. IEEE Transactions on Neural Networks. 15 (2004): 1135-50. [42] Dong R. Perceptual Binaural Speech Enhancement in Noisy Environments. M.A.Sc

T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia.

PubMed

Alachkar, Houda; Mutonga, Martin; Malnassy, Gregory; Park, Jae-Hyun; Fulton, Noreen; Woods, Alex; Meng, Liping; Kline, Justin; Raca, Gordana; Odenike, Olatoyosi; Takamatsu, Naofumi; Miyamoto, Takashi; Matsuo, Yo; Stock, Wendy; Nakamura, Yusuke

2015-10-20

Gain-of-function mutations of FLT3 (FLT3-ITD), comprises up to 30% of normal karyotype acute myeloid leukemia (AML) and is associated with an adverse prognosis. Current FLT3 kinase inhibitors have been tested extensively, but have not yet resulted in a survival benefit and novel therapies are awaited. Here we show that T-LAK cell-originated protein kinase (TOPK), a mitotic kinase highly expressed in and correlated with more aggressive phenotype in several types of cancer, is expressed in AML but not in normal CD34+ cells and that TOPK knockdown decreased cell viability and induced apoptosis. Treatment of AML cells with TOPK inhibitor (OTS514) resulted in a dose-dependent decrease in cell viability with lower IC50 in FLT3-mutated cells, including blasts obtained from patients relapsed after FLT3-inhibitor treatment. Using a MV4-11-engrafted mouse model, we found that mice treated with 7.5 mg/kg IV daily for 3 weeks survived significantly longer than vehicle treated mice (median survival 46 vs 29 days, P < 0.001). Importantly, we identified TOPK as a FLT3-ITD and CEBPA regulated kinase, and that modulating TOPK expression or activity resulted in significant decrease of FLT3 expression and CEBPA phosphorylation. Thus, targeting TOPK in FLT3-ITD AML represents a novel therapeutic approach for this adverse risk subset of AML.

Treatment of non-traumatic out-of-hospital cardiac arrest with active compression decompression cardiopulmonary resuscitation plus an impedance threshold device.

PubMed

Frascone, Ralph J; Wayne, Marvin A; Swor, Robert A; Mahoney, Brian D; Domeier, Robert M; Olinger, Michael L; Tupper, David E; Setum, Cindy M; Burkhart, Nathan; Klann, Lucinda; Salzman, Joshua G; Wewerka, Sandi S; Yannopoulos, Demetris; Lurie, Keith G; O'Neil, Brian J; Holcomb, Richard G; Aufderheide, Tom P

2013-09-01

A recent out-of-hospital cardiac arrest (OHCA) clinical trial showed improved survival to hospital discharge (HD) with favorable neurologic function for patients with cardiac arrest of cardiac origin treated with active compression decompression cardiopulmonary resuscitation (CPR) plus an impedance threshold device (ACD+ICD) versus standard (S) CPR. The current analysis examined whether treatment with ACD+ITD is more effective than standard (S-CPR) for all cardiac arrests of non-traumatic origin, regardless of the etiology. This is a secondary analysis of data from a randomized, prospective, multicenter, intention-to-treat, OHCA clinical trial. Adults with presumed non-traumatic cardiac arrest were enrolled and followed for one year post arrest. The primary endpoint was survival to hospital discharge (HD) with favorable neurologic function (Modified Rankin Scale score ≤ 3). Between October 2005 and July 2009, 2738 patients were enrolled (S-CPR=1335; ACD+ITD=1403). Survival to HD with favorable neurologic function was greater with ACD+ITD compared with S-CPR: 7.9% versus 5.7%, (OR 1.42, 95% CI 1.04, 1.95, p=0.027). One-year survival was also greater: 7.9% versus 5.7%, (OR 1.43, 95% CI 1.04, 1.96, p=0.026). Nearly all survivors in both groups had returned to their baseline neurological function by one year. Major adverse event rates were similar between groups. Treatment of out-of-hospital non-traumatic cardiac arrest patients with ACD+ITD resulted in a significant increase in survival to hospital discharge with favorable neurological function when compared with S-CPR. A significant increase survival rates was observed up to one year after arrest in subjects treated with ACD+ITD, regardless of the etiology of the cardiac arrest. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Feature genes predicting the FLT3/ITD mutation in acute myeloid leukemia

PubMed Central

LI, CHENGLONG; ZHU, BIAO; CHEN, JIAO; HUANG, XIAOBING

2016-01-01

In the present study, gene expression profiles of acute myeloid leukemia (AML) samples were analyzed to identify feature genes with the capacity to predict the mutation status of FLT3/ITD. Two machine learning models, namely the support vector machine (SVM) and random forest (RF) methods, were used for classification. Four datasets were downloaded from the European Bioinformatics Institute, two of which (containing 371 samples, including 281 FLT3/ITD mutation-negative and 90 mutation-positive samples) were randomly defined as the training group, while the other two datasets (containing 488 samples, including 350 FLT3/ITD mutation-negative and 138 mutation-positive samples) were defined as the test group. Differentially expressed genes (DEGs) were identified by significance analysis of the micro-array data by using the training samples. The classification efficiency of the SCM and RF methods was evaluated using the following parameters: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the area under the receiver operating characteristic curve. Functional enrichment analysis was performed for the feature genes with DAVID. A total of 585 DEGs were identified in the training group, of which 580 were upregulated and five were downregulated. The classification accuracy rates of the two methods for the training group, the test group and the combined group using the 585 feature genes were >90%. For the SVM and RF methods, the rates of correct determination, specificity and PPV were >90%, while the sensitivity and NPV were >80%. The SVM method produced a slightly better classification effect than the RF method. A total of 13 biological pathways were overrepresented by the feature genes, mainly involving energy metabolism, chromatin organization and translation. The feature genes identified in the present study may be used to predict the mutation status of FLT3/ITD in patients with AML. PMID:27177049

Phase I Trial of Maintenance Sorafenib after Allogeneic Hematopoietic Stem Cell Transplantation for FLT3-ITD AML

PubMed Central

Chen, Yi-Bin; Li, Shuli; Lane, Andrew A.; Connolly, Christine; Del Rio, Candice; Valles, Betsy; Curtis, Morgan; Ballen, Karen; Cutler, Corey; Dey, Bimalangshu R.; El-Jawahri, Areej; Fathi, Amir T.; Ho, Vincent T.; Joyce, Amy; McAfee, Steven; Rudek, Michelle; Rajkhowa, Trivikram; Verselis, Sigitas; Antin, Joseph H.; Spitzer, Thomas R.; Levis, Mark; Soiffer, Robert

2014-01-01

The FLT3-ITD mutation is associated with a high relapse rate for patients with AML even after allogeneic hematopoietic stem cell transplantation (HSCT). Sorafenib is a tyrosine kinase inhibitor which inhibits the FLT3 tyrosine kinase and has shown encouraging activity in FLT3-ITD AML. We conducted a phase I trial of maintenance sorafenib after HSCT in patients with FLT3-ITD AML (ClinicalTrials.gov NCT01398501). Patients received a variety of conditioning regimens and graft sources. A dose escalation 3+3 cohort design was used to define the maximum tolerated dose (MTD) with an additional 10 patients treated at the MTD. Sorafenib was initiated between days 45 and 120 after HSCT continued for twelve 28-day cycles. Twenty-two patients were enrolled (status at HSCT: CR1=16, CR2=3, refractory=3). The MTD was established at 400 mg BID with one DLT observed (pericardial effusion). Two patients died of transplant-related causes, both unrelated to sorafenib. Two patients stopped sorafenib after relapse and 5 stopped due to attributable toxicities after the DLT period. Median follow-up for surviving patients is 16.7 months after HSCT (range, 8.1–35.0). There was one case of grade II acute GVHD after starting sorafenib and the 12-month cumulative incidence of chronic GVHD was 38% (90% CI, 21%–56%). For all patients, one-year progression-free survival (PFS) is 85% (90% CI, 66%–94%) and one-year overall survival (OS) is 95% (90% CI, 79%–99%) after HSCT. For patients in CR1 / CR2 prior to HSCT (n=19), one-year PFS is 95% (90% CI, 76%–99%) and one-year OS is 100% with only one patient who has relapsed. Sorafenib is safe after HSCT for FLT3-ITD AML and merits further investigation for the prevention of relapse. PMID:25239228

Feature genes predicting the FLT3/ITD mutation in acute myeloid leukemia.

PubMed

Li, Chenglong; Zhu, Biao; Chen, Jiao; Huang, Xiaobing

2016-07-01

In the present study, gene expression profiles of acute myeloid leukemia (AML) samples were analyzed to identify feature genes with the capacity to predict the mutation status of FLT3/ITD. Two machine learning models, namely the support vector machine (SVM) and random forest (RF) methods, were used for classification. Four datasets were downloaded from the European Bioinformatics Institute, two of which (containing 371 samples, including 281 FLT3/ITD mutation-negative and 90 mutation‑positive samples) were randomly defined as the training group, while the other two datasets (containing 488 samples, including 350 FLT3/ITD mutation-negative and 138 mutation-positive samples) were defined as the test group. Differentially expressed genes (DEGs) were identified by significance analysis of the microarray data by using the training samples. The classification efficiency of the SCM and RF methods was evaluated using the following parameters: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the area under the receiver operating characteristic curve. Functional enrichment analysis was performed for the feature genes with DAVID. A total of 585 DEGs were identified in the training group, of which 580 were upregulated and five were downregulated. The classification accuracy rates of the two methods for the training group, the test group and the combined group using the 585 feature genes were >90%. For the SVM and RF methods, the rates of correct determination, specificity and PPV were >90%, while the sensitivity and NPV were >80%. The SVM method produced a slightly better classification effect than the RF method. A total of 13 biological pathways were overrepresented by the feature genes, mainly involving energy metabolism, chromatin organization and translation. The feature genes identified in the present study may be used to predict the mutation status of FLT3/ITD in patients with AML.

Treatment of Non-Traumatic Out-of-Hospital Cardiac Arrest with Active Compression Decompression Cardiopulmonary Resuscitation plus an Impedance Threshold Device

PubMed Central

Frascone, Ralph J; Wayne, Marvin A; Swor, Robert A; Mahoney, Brian D; Domeier, Robert M; Olinger, Michael L; Tupper, David E; Setum, Cindy M; Burkhart, Nathan; Klann, Lucinda; Salzman, Joshua G; Wewerka, Sandi S; Yannopoulos, Demetris; Lurie, Keith G; O’Neil, Brian J.; Holcomb, Richard G; Aufderheide, Tom P

2013-01-01

Background A recent out-of-hospital cardiac arrest (OHCA) clinical trial showed improved survival to hospital discharge (HD) with favorable neurologic function for patients with cardiac arrest of cardiac origin treated with active compression decompression cardiopulmonary resuscitation (CPR) plus an impedance threshold device (ACD+ICD) versus standard (S) CPR. The current analysis examined whether treatment with ACD+ITD is more effective than standard (S-CPR) for all cardiac arrests of non-traumatic origin, regardless of the aetiology. Methods This is a secondary analysis of data from a randomized, prospective, multicenter, intention-to-treat, OHCA clinical trial. Adults with presumed non-traumatic cardiac arrest were enrolled and followed for one year post arrest. The primary endpoint was survival to hospital discharge (HD) with favorable neurologic function (modified Rankin Scale score ≤3). Results Between October 2005 to July 2009, 2738 patients were enrolled (S-CPR = 1335; ACD+ITD =1403). Survival to HD with favorable neurologic function was greater with ACD+ITD compared with S-CPR: 7.9% versus 5.7%, (OR 1.42, 95% CI 1.04, 1.95, p=0.027). One-year survival was also greater: 7.9% versus 5.7%, (OR 1.43, 95% CI 1.04, 1.96, p=0.026). Nearly all survivors in both groups had returned to their baseline neurological function by one year. Major adverse event rates were similar between groups. Conclusions Treatment of out-of-hospital non-traumatic cardiac arrest patients with ACD+ITD resulted in a significant increase in survival to hospital discharge with favorable neurological function when compared with S-CPR. A significant increase survival rates was observed up to one year after arrest in subjects treated with ACD+ITD, regardless of the etiology of the cardiac arrest. Clinical Trial Registration NCT 00189423 (http://www.clinicaltrials.gov) PMID:23669489

Use of an Impedance Threshold Device in Spontaneously Breathing Patients with Hypotension Secondary to Trauma: An Observational Cohort Feasibility Study

DTIC Science & Technology

2014-09-09

hypotensive patient. Crystalloid infusion is not necessarily benign.1,2 Difficult vascular access, hemodilution, acidosis , decreased oxygen delivery, and...blood pressure, heart rate (HR), respiratory rate, and arterial oxygen saturation (SpO2) were recorded im- mediately before application of the ITD...per minute (p = 0.007). The respiratory rate was constant: 19 (7) breaths before to 18 (4) breaths (p = 0.31) per minute after ITD use. Oxygen

T-LAK cell-originated protein kinase presents a novel therapeutic target in FLT3-ITD mutated acute myeloid leukemia

PubMed Central

Alachkar, Houda; Mutonga, Martin; Malnassy, Gregory; Park, Jae-Hyun; Fulton, Noreen; Woods, Alex; Meng, Liping; Kline, Justin; Raca, Gordana; Odenike, Olatoyosi; Takamatsu, Naofumi; Miyamoto, Takashi; Matsuo, Yo; Stock, Wendy; Nakamura, Yusuke

2015-01-01

Gain-of-function mutations of FLT3 (FLT3-ITD), comprises up to 30% of normal karyotype acute myeloid leukemia (AML) and is associated with an adverse prognosis. Current FLT3 kinase inhibitors have been tested extensively, but have not yet resulted in a survival benefit and novel therapies are awaited. Here we show that T-LAK cell-originated protein kinase (TOPK), a mitotic kinase highly expressed in and correlated with more aggressive phenotype in several types of cancer, is expressed in AML but not in normal CD34+ cells and that TOPK knockdown decreased cell viability and induced apoptosis. Treatment of AML cells with TOPK inhibitor (OTS514) resulted in a dose-dependent decrease in cell viability with lower IC50 in FLT3-mutated cells, including blasts obtained from patients relapsed after FLT3-inhibitor treatment. Using a MV4-11-engrafted mouse model, we found that mice treated with 7.5 mg/kg IV daily for 3 weeks survived significantly longer than vehicle treated mice (median survival 46 vs 29 days, P < 0.001). Importantly, we identified TOPK as a FLT3-ITD and CEBPA regulated kinase, and that modulating TOPK expression or activity resulted in significant decrease of FLT3 expression and CEBPA phosphorylation. Thus, targeting TOPK in FLT3-ITD AML represents a novel therapeutic approach for this adverse risk subset of AML. PMID:26450903

FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia

PubMed Central

Kim, Hyung-Gyoon; Kojima, Kyoko; Swindle, C. Scott; Cotta, Claudiu V.; Huo, Yongliang; Reddy, Vishnu

2008-01-01

The inversion of chromosome 16 in the inv(16)(p13q22) is one of the most frequent cytogenetic abnormalities observed in acute myeloid leukemia (AML). The inv(16) fuses the core binding factor (CBF) beta subunit with the coiled-coil rod domain of smooth muscle myosin heavy chain (SMMHC). Expression of CBFβ-SMMHC in mice does not promote AML in the absence of secondary mutations. Patient samples with the inv(16) also possess mutually exclusive activating mutations in either N-RAS, K-RAS, or the receptor tyrosine kinases, c-KIT and FLT3, in almost 70% of cases. To test whether an activating mutation of FLT3 (FLT3-ITD) would cooperate with CBFβ-SMMHC to promote AML, we coexpressed both mutations in hematopoietic progenitor cells used to reconstitute lethally irradiated mice. Analysis of transplanted animals showed strong selection for CBFβ-SMMHC/FLT3-ITD–expressing cells in bone marrow and peripheral blood. Compared with animals transplanted with only CBFβ-SMMHC–expressing cells, FLT3-ITD further restricted early myeloid differentiation and promoted peripheralization of primitive myeloblasts as early as 2.5 weeks after transplantation. FLT3-ITD also accelerated disease progression in all CBFβ-SMMHC/FLT3-ITD–reconstituted animals, which died of a highly aggressive and transplantable AML within 3 to 5 months. These results indicate that FLT3-activating mutations can cooperate with CBFβ-SMMHC in an animal model of inv(16)-associated AML. PMID:17967943

CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib.

PubMed

Jetani, Hardikkumar; Garcia-Cadenas, Irene; Nerreter, Thomas; Thomas, Simone; Rydzek, Julian; Meijide, Javier Briones; Bonig, Halvard; Herr, Wolfgang; Sierra, Jordi; Einsele, Hermann; Hudecek, Michael

2018-05-01

FMS-like tyrosine kinase 3 (FLT3) is a transmembrane protein expressed on normal hematopoietic stem and progenitor cells (HSC) and retained on malignant blasts in acute myeloid leukemia (AML). We engineered CD8 + and CD4 + T-cells expressing a FLT3-specific chimeric antigen receptor (CAR) and demonstrate they confer potent reactivity against AML cell lines and primary AML blasts that express either wild-type FLT3 or FLT3 with internal tandem duplication (FLT3-ITD). We also show that treatment with the FLT3-inhibitor crenolanib leads to increased surface expression of FLT3 specifically on FLT3-ITD + AML cells and consecutively, enhanced recognition by FLT3-CAR T-cells in vitro and in vivo. As anticipated, we found that FLT3-CAR T-cells recognize normal HSCs in vitro and in vivo, and disrupt normal hematopoiesis in colony-formation assays, suggesting that adoptive therapy with FLT3-CAR T-cells will require subsequent CAR T-cell depletion and allogeneic HSC transplantation to reconstitute the hematopoietic system. Collectively, our data establish FLT3 as a novel CAR target in AML with particular relevance in high-risk FLT3-ITD + AML. Further, our data provide the first proof-of-concept that CAR T-cell immunotherapy and small molecule inhibition can be used synergistically, as exemplified by our data showing superior antileukemia efficacy of FLT3-CAR T-cells in combination with crenolanib.

BCOR Overexpression Is a Highly Sensitive Marker in Round Cell Sarcomas With BCOR Genetic Abnormalities.

PubMed

Kao, Yu-Chien; Sung, Yun-Shao; Zhang, Lei; Jungbluth, Achim A; Huang, Shih-Chiang; Argani, Pedram; Agaram, Narasimhan P; Zin, Angelica; Alaggio, Rita; Antonescu, Cristina R

2016-12-01

With the advent of next-generation sequencing, an increasing number of novel gene fusions and other abnormalities have emerged recently in the spectrum of EWSR1-negative small blue round cell tumors (SBRCTs). In this regard, a subset of SBRCTs harboring either BCOR gene fusions (BCOR-CCNB3, BCOR-MAML3), BCOR internal tandem duplications (ITD), or YWHAE-NUTM2B share a transcriptional signature including high BCOR mRNA expression, as well as similar histologic features. Furthermore, other tumors such as clear cell sarcoma of kidney (CCSK) and primitive myxoid mesenchymal tumor of infancy also demonstrate BCOR ITDs and high BCOR gene expression. The molecular diagnosis of these various BCOR genetic alterations requires an elaborate methodology including custom BAC fluorescence in situ hybridization (FISH) probes and reverse transcription polymerase chain reaction assays. As these tumors show high level of BCOR overexpression regardless of the genetic mechanism involved, either conventional gene fusion or ITD, we sought to investigate the performance of an anti-BCOR monoclonal antibody clone C-10 (sc-514576) as an immunohistochemical marker for sarcomas with BCOR gene abnormalities. Thus we assessed the BCOR expression in a pathologically and genetically well-characterized cohort of 25 SBRCTs, spanning various BCOR-related fusions and ITDs and YWHAE-NUTM2B fusion. In addition, we included related pathologic entities such as 8 CCSKs and other sarcomas with BCOR gene fusions. As a control group we included 20 SBRCTs with various (non-BCOR) genetic abnormalities, 10 fusion-negative SBRCTs, 74 synovial sarcomas, 29 rhabdomyosarcomas, and other sarcoma types. In addition, we evaluated the same study group for SATB2 immunoreactivity, as these tumors also showed SATB2 mRNA upregulation. All SBRCTs with BCOR-MAML3 and BCOR-CCNB3 fusions, as well as most with BCOR ITD (93%), and all CCSKs showed strong and diffuse nuclear BCOR immunoreactivity. Furthermore, all SBRCTs with YWHAE-NUTM2B also were positive. SATB2 stain was also positive in tumors with YWHAE-NUTM2B, BCOR-MAML3, BCOR ITD (75%), BCOR-CCNB3 (71%), and a subset of CCSKs (33%). In conclusion, BCOR immunohistochemical stain is a highly sensitive marker for SBRCTs and CCSKs with BCOR abnormalities and YWHAE-rearrangements and can be used as a useful diagnostic marker in these various molecular subsets. SATB2 immunoreactivity is also present in the majority of this group of tumors.

NASA Environmentally Responsible Aviation's Highly-Loaded Front Block Compressor Demonstration

NASA Technical Reports Server (NTRS)

Celestina, Mark

2017-01-01

The ERA project was created in 2009 as part of NASAs Aeronautics Research Mission Directorates (ARMD) Integrated Systems Aviation Program (IASP). The purpose of the ERA project was to explore and document the feasibility, benefit, and technical risk of vehicles concepts and enabling technologies to reduce aviations impact on the environment. The metrics for this technology is given in Figure 1 with the N+2 metrics highlighted in green. It is anticipated that the United States air transportation system will continue to expand significantly over the next few decades thus adversely impacting the environment unless new technology is incorporated to simultaneously reduce nitrous oxides (NOx), noise and fuel consumption. In order to achieve the overall goals and meet the technology insertion challenges, these goals were divided into technical challenges that were to be achieved during the execution of the ERA project. Technical challenges were accomplished through test campaigns conducted by Integrated Technology Demonstration (ITDs). ERAs technical performance period ended in 2015.

Quality of CPR: An important effect modifier in cardiac arrest clinical outcomes and intervention effectiveness trials.

PubMed

Yannopoulos, Demetris; Aufderheide, Tom P; Abella, Benjamin S; Duval, Sue; Frascone, Ralph J; Goodloe, Jeffrey M; Mahoney, Brian D; Nadkarni, Vinay M; Halperin, Henry R; O'Connor, Robert; Idris, Ahamed H; Becker, Lance B; Pepe, Paul E

2015-09-01

To determine if the quality of CPR had a significant interaction with the primary study intervention in the NIH PRIMED trial. The public access database from the NIH PRIMED trial was accessed to determine if there was an interaction between quality of CPR performance, intervention, and outcome (survival to hospital discharge with modified Rankin Score (mRS) ≤ 3). Multi-centered prehospital care systems across North America. Of 8719 adult patients enrolled, CPR quality was electronically recorded for compression rate, depth, and fraction in 6199 (71.1%), 3750 (43.0%) and 6204 (71.2%) subjects, respectively. "Acceptable" quality CPR was defined prospectively as simultaneous provision of a compression rate of 100/min (± 20%), depth of 5 cm (± 20%) and fraction of > 50%. Significant interaction was considered as p < 0.05. Standard CPR with an activated versus sham (inactivated) ITD. Overall, 848 and 827 patients, respectively, in the active and sham-ITD groups had "acceptable" CPR quality performed (n = 1675). There was a significant interaction between the active and sham-ITD and compression rate, depth and fraction as well as their combinations. The strongest interaction was seen with all three parameters combined (unadjusted and adjusted interaction p-value, < 0.001). For all presenting rhythms, when "acceptable" quality of CPR was performed, use of an active-ITD increased survival to hospital discharge with mRS ≤ 3 compared to sham (61/848 [7.2%] versus 34/827 [4.1%], respectively; p = 0.006). The opposite was true for patients that did not receive "acceptable" quality of CPR. In those patients, use of an active - ITD led to significantly worse survival to hospital discharge with mRS ≤ 3 compared to sham (34/1012 [3.4%] versus 62/1061 [5.8%], p = 0.007). There was a statistically significant interaction between the quality of CPR provided, intervention, and survival to hospital discharge with mRS ≤ 3 in the NIH PRIMED trial. Quality of CPR delivered can be an underestimated effect modifier in CPR clinical trials. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Functional Characterization of FLT3 Receptor Signaling Deregulation in Acute Myeloid Leukemia by Single Cell Network Profiling (SCNP)

PubMed Central

Rosen, David B.; Minden, Mark D.; Kornblau, Steven M.; Cohen, Aileen; Gayko, Urte; Putta, Santosh; Woronicz, John; Evensen, Erik; Fantl, Wendy J.; Cesano, Alessandra

2010-01-01

Background Molecular characterization of the FMS-like tyrosine kinase 3 receptor (FLT3) in cytogenetically normal acute myeloid leukemia (AML) has recently been incorporated into clinical guidelines based on correlations between FLT3 internal tandem duplications (FLT3-ITD) and decreased disease-free and overall survival. These mutations result in constitutive activation of FLT3, and FLT3 inhibitors are currently undergoing trials in AML patients selected on FLT3 molecular status. However, the transient and partial responses observed suggest that FLT3 mutational status alone does not provide complete information on FLT3 biological activity at the individual patient level. Examination of variation in cellular responsiveness to signaling modulation may be more informative. Methodology/Principal Findings Using single cell network profiling (SCNP), cells were treated with extracellular modulators and their functional responses were quantified by multiparametric flow cytometry. Intracellular signaling responses were compared between healthy bone marrow myeloblasts (BMMb) and AML leukemic blasts characterized as FLT3 wild type (FLT3-WT) or FLT3-ITD. Compared to healthy BMMb, FLT3-WT leukemic blasts demonstrated a wide range of signaling responses to FLT3 ligand (FLT3L), including elevated and sustained PI3K and Ras/Raf/Erk signaling. Distinct signaling and apoptosis profiles were observed in FLT3-WT and FLT3-ITD AML samples, with more uniform signaling observed in FLT3-ITD AML samples. Specifically, increased basal p-Stat5 levels, decreased FLT3L induced activation of the PI3K and Ras/Raf/Erk pathways, decreased IL-27 induced activation of the Jak/Stat pathway, and heightened apoptotic responses to agents inducing DNA damage were observed in FLT3-ITD AML samples. Preliminary analysis correlating these findings with clinical outcomes suggests that classification of patient samples based on signaling profiles may more accurately reflect FLT3 signaling deregulation and provide additional information for disease characterization and management. Conclusions/Significance These studies show the feasibility of SCNP to assess modulated intracellular signaling pathways and characterize the biology of individual AML samples in the context of genetic alterations. PMID:21048955

Evidence for cue-independent spatial representation in the human auditory cortex during active listening.

PubMed

Higgins, Nathan C; McLaughlin, Susan A; Rinne, Teemu; Stecker, G Christopher

2017-09-05

Few auditory functions are as important or as universal as the capacity for auditory spatial awareness (e.g., sound localization). That ability relies on sensitivity to acoustical cues-particularly interaural time and level differences (ITD and ILD)-that correlate with sound-source locations. Under nonspatial listening conditions, cortical sensitivity to ITD and ILD takes the form of broad contralaterally dominated response functions. It is unknown, however, whether that sensitivity reflects representations of the specific physical cues or a higher-order representation of auditory space (i.e., integrated cue processing), nor is it known whether responses to spatial cues are modulated by active spatial listening. To investigate, sensitivity to parametrically varied ITD or ILD cues was measured using fMRI during spatial and nonspatial listening tasks. Task type varied across blocks where targets were presented in one of three dimensions: auditory location, pitch, or visual brightness. Task effects were localized primarily to lateral posterior superior temporal gyrus (pSTG) and modulated binaural-cue response functions differently in the two hemispheres. Active spatial listening (location tasks) enhanced both contralateral and ipsilateral responses in the right hemisphere but maintained or enhanced contralateral dominance in the left hemisphere. Two observations suggest integrated processing of ITD and ILD. First, overlapping regions in medial pSTG exhibited significant sensitivity to both cues. Second, successful classification of multivoxel patterns was observed for both cue types and-critically-for cross-cue classification. Together, these results suggest a higher-order representation of auditory space in the human auditory cortex that at least partly integrates the specific underlying cues.

Evidence for cue-independent spatial representation in the human auditory cortex during active listening

PubMed Central

McLaughlin, Susan A.; Rinne, Teemu; Stecker, G. Christopher

2017-01-01

Few auditory functions are as important or as universal as the capacity for auditory spatial awareness (e.g., sound localization). That ability relies on sensitivity to acoustical cues—particularly interaural time and level differences (ITD and ILD)—that correlate with sound-source locations. Under nonspatial listening conditions, cortical sensitivity to ITD and ILD takes the form of broad contralaterally dominated response functions. It is unknown, however, whether that sensitivity reflects representations of the specific physical cues or a higher-order representation of auditory space (i.e., integrated cue processing), nor is it known whether responses to spatial cues are modulated by active spatial listening. To investigate, sensitivity to parametrically varied ITD or ILD cues was measured using fMRI during spatial and nonspatial listening tasks. Task type varied across blocks where targets were presented in one of three dimensions: auditory location, pitch, or visual brightness. Task effects were localized primarily to lateral posterior superior temporal gyrus (pSTG) and modulated binaural-cue response functions differently in the two hemispheres. Active spatial listening (location tasks) enhanced both contralateral and ipsilateral responses in the right hemisphere but maintained or enhanced contralateral dominance in the left hemisphere. Two observations suggest integrated processing of ITD and ILD. First, overlapping regions in medial pSTG exhibited significant sensitivity to both cues. Second, successful classification of multivoxel patterns was observed for both cue types and—critically—for cross-cue classification. Together, these results suggest a higher-order representation of auditory space in the human auditory cortex that at least partly integrates the specific underlying cues. PMID:28827357

Behavioural sensitivity to binaural spatial cues in ferrets: evidence for plasticity in the duplex theory of sound localization

PubMed Central

Keating, Peter; Nodal, Fernando R; King, Andrew J

2014-01-01

For over a century, the duplex theory has guided our understanding of human sound localization in the horizontal plane. According to this theory, the auditory system uses interaural time differences (ITDs) and interaural level differences (ILDs) to localize low-frequency and high-frequency sounds, respectively. Whilst this theory successfully accounts for the localization of tones by humans, some species show very different behaviour. Ferrets are widely used for studying both clinical and fundamental aspects of spatial hearing, but it is not known whether the duplex theory applies to this species or, if so, to what extent the frequency range over which each binaural cue is used depends on acoustical or neurophysiological factors. To address these issues, we trained ferrets to lateralize tones presented over earphones and found that the frequency dependence of ITD and ILD sensitivity broadly paralleled that observed in humans. Compared with humans, however, the transition between ITD and ILD sensitivity was shifted toward higher frequencies. We found that the frequency dependence of ITD sensitivity in ferrets can partially be accounted for by acoustical factors, although neurophysiological mechanisms are also likely to be involved. Moreover, we show that binaural cue sensitivity can be shaped by experience, as training ferrets on a 1-kHz ILD task resulted in significant improvements in thresholds that were specific to the trained cue and frequency. Our results provide new insights into the factors limiting the use of different sound localization cues and highlight the importance of sensory experience in shaping the underlying neural mechanisms. PMID:24256073

Time-Varying Distortions of Binaural Information by Bilateral Hearing Aids

PubMed Central

Rodriguez, Francisco A.; Portnuff, Cory D. F.; Goupell, Matthew J.; Tollin, Daniel J.

2016-01-01

In patients with bilateral hearing loss, the use of two hearing aids (HAs) offers the potential to restore the benefits of binaural hearing, including sound source localization and segregation. However, existing evidence suggests that bilateral HA users’ access to binaural information, namely interaural time and level differences (ITDs and ILDs), can be compromised by device processing. Our objective was to characterize the nature and magnitude of binaural distortions caused by modern digital behind-the-ear HAs using a variety of stimuli and HA program settings. Of particular interest was a common frequency-lowering algorithm known as nonlinear frequency compression, which has not previously been assessed for its effects on binaural information. A binaural beamforming algorithm was also assessed. Wide dynamic range compression was enabled in all programs. HAs were placed on a binaural manikin, and stimuli were presented from an arc of loudspeakers inside an anechoic chamber. Stimuli were broadband noise bursts, 10-Hz sinusoidally amplitude-modulated noise bursts, or consonant–vowel–consonant speech tokens. Binaural information was analyzed in terms of ITDs, ILDs, and interaural coherence, both for whole stimuli and in a time-varying sense (i.e., within a running temporal window) across four different frequency bands (1, 2, 4, and 6 kHz). Key findings were: (a) Nonlinear frequency compression caused distortions of high-frequency envelope ITDs and significantly reduced interaural coherence. (b) For modulated stimuli, all programs caused time-varying distortion of ILDs. (c) HAs altered the relationship between ITDs and ILDs, introducing large ITD–ILD conflicts in some cases. Potential perceptual consequences of measured distortions are discussed. PMID:27698258

Revision of Import and Export Requirements for Controlled Substances, Listed Chemicals, and Tableting and Encapsulating Machines, Including Changes To Implement the International Trade Data System (ITDS); Revision of Reporting Requirements for Domestic Transactions in Listed Chemicals and Tableting and Encapsulating Machines; and Technical Amendments. Final rule.

PubMed

2016-12-30

The Drug Enforcement Administration is updating its regulations for the import and export of tableting and encapsulating machines, controlled substances, and listed chemicals, and its regulations relating to reports required for domestic transactions in listed chemicals, gamma-hydroxybutyric acid, and tableting and encapsulating machines. In accordance with Executive Order 13563, the Drug Enforcement Administration has reviewed its import and export regulations and reporting requirements for domestic transactions in listed chemicals (and gamma-hydroxybutyric acid) and tableting and encapsulating machines, and evaluated them for clarity, consistency, continued accuracy, and effectiveness. The amendments clarify certain policies and reflect current procedures and technological advancements. The amendments also allow for the implementation, as applicable to tableting and encapsulating machines, controlled substances, and listed chemicals, of the President's Executive Order 13659 on streamlining the export/import process and requiring the government-wide utilization of the International Trade Data System (ITDS). This rule additionally contains amendments that implement recent changes to the Controlled Substances Import and Export Act (CSIEA) for reexportation of controlled substances among members of the European Economic Area made by the Improving Regulatory Transparency for New Medical Therapies Act. The rule also includes additional substantive and technical and stylistic amendments.

MIZMAS: Modeling the Evolution of Ice Thickness and Floe Size Distributions in the Marginal Ice Zone of the Chukchi and Beaufort Seas

DTIC Science & Technology

2014-09-30

existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this...through downscaling future projection simulations. APPROACH To address the scientific objectives, we plan to develop, implement, and validate a...ITD and FSD at the same time. The development of MIZMAS will be based on systematic model parameterization, calibration, and validation, and data

Biometric and structural ocular manifestations of Marfan syndrome.

PubMed

Gehle, Petra; Goergen, Barbara; Pilger, Daniel; Ruokonen, Peter; Robinson, Peter N; Salchow, Daniel J

2017-01-01

To study biometric and structural ocular manifestations of Marfan syndrome (MFS). Observational, retrospective, comparative cohort study in a tertiary referral center on 285 MFS patients and 267 controls. Structural and biometric ocular characteristic were compared. MFS eyes were longer (axial length 24.25 ± 1.74 mm versus 23.89 ± 1.31 mm, p < 0.001) and had a flatter cornea than control eyes (mean keratometry 41.78 ± 1.80 diopters (D) versus 43.05 ± 1.51 D, p < 0.001). Corneal astigmatism was greater and the central cornea was thinner in MFS eyes (530.14 ± 41.31 μm versus 547.02 ± 39.18 μm, p < 0.001). MFS eyes were more myopic than control eyes (spherical equivalent -2.16 ± 3.75 D versus -1.17 ± 2.58 D, p < 0.001). Visual acuity was reduced (0.13 ± 0.25 logMAR versus 0.05 ± 0.18 logMAR, p < 0.001) and intraocular pressure was lower in MFS eyes (14.6 ± 3.4 mmHg versus 15.1 ± 3.2 mmHg, p = 0.01). Iris transillumination defects (ITD) were significantly more common in MFS eyes (odds ratio for MFS in the presence of ITD, 3.7). Ectopia lentis (EL) was only present in MFS eyes (33.4%). History of retinal detachment was significantly more common in MFS eyes. Glaucoma was equally common in both groups. ITD and EL are most characteristic findings in MFS. ITD and corneal curvature should be studied as diagnostic criteria for MFS. Visual acuity is reduced in MFS. MFS patients need regular eye exams to identify serious ocular complications.

Biometric and structural ocular manifestations of Marfan syndrome

PubMed Central

Gehle, Petra; Goergen, Barbara; Pilger, Daniel; Ruokonen, Peter; Robinson, Peter N.

2017-01-01

Background To study biometric and structural ocular manifestations of Marfan syndrome (MFS). Methods Observational, retrospective, comparative cohort study in a tertiary referral center on 285 MFS patients and 267 controls. Structural and biometric ocular characteristic were compared. Results MFS eyes were longer (axial length 24.25 ± 1.74 mm versus 23.89 ± 1.31 mm, p < 0.001) and had a flatter cornea than control eyes (mean keratometry 41.78 ± 1.80 diopters (D) versus 43.05 ± 1.51 D, p < 0.001). Corneal astigmatism was greater and the central cornea was thinner in MFS eyes (530.14 ± 41.31 μm versus 547.02 ± 39.18 μm, p < 0.001). MFS eyes were more myopic than control eyes (spherical equivalent -2.16 ± 3.75 D versus -1.17 ± 2.58 D, p < 0.001). Visual acuity was reduced (0.13 ± 0.25 logMAR versus 0.05 ± 0.18 logMAR, p < 0.001) and intraocular pressure was lower in MFS eyes (14.6 ± 3.4 mmHg versus 15.1 ± 3.2 mmHg, p = 0.01). Iris transillumination defects (ITD) were significantly more common in MFS eyes (odds ratio for MFS in the presence of ITD, 3.7). Ectopia lentis (EL) was only present in MFS eyes (33.4%). History of retinal detachment was significantly more common in MFS eyes. Glaucoma was equally common in both groups. Conclusions ITD and EL are most characteristic findings in MFS. ITD and corneal curvature should be studied as diagnostic criteria for MFS. Visual acuity is reduced in MFS. MFS patients need regular eye exams to identify serious ocular complications. PMID:28931008

Evaluation of the kinase domain of c-KIT in canine cutaneous mast cell tumors

PubMed Central

Webster, Joshua D; Kiupel, Matti; Yuzbasiyan-Gurkan, Vilma

2006-01-01

Background Mutations in the c-KIT proto-oncogene have been implicated in the progression of several neoplastic diseases, including gastrointestinal stromal tumors and mastocytosis in humans, and cutaneous mast cell tumors (MCTs) in canines. Mutations in human mastocytosis patients primarily occur in c-KIT exon 17, which encodes a portion of its kinase domain. In contrast, deletions and internal tandem duplication (ITD) mutations are found in the juxtamembrane domain of c-KIT in approximately 15% of canine MCTs. In addition, ITD c-KIT mutations are significantly associated with aberrant KIT protein localization in canine MCTs. However, some canine MCTs have aberrant KIT localization but lack ITD c-KIT mutations, suggesting that other mutations or other factors may be responsible for aberrant KIT localization in these tumors. Methods In order to characterize the prevalence of mutations in the phospho-transferase portion of c-KIT's kinase domain in canine MCTs exons 16–20 of 33 canine MCTs from 33 dogs were amplified and sequenced. Additionally, in order to determine if mutations in c-KIT exon 17 are responsible for aberrant KIT localization in MCTs that lack juxtamembrane domain c-KIT mutations, c-KIT exon 17 was amplified and sequenced from 18 canine MCTs that showed an aberrant KIT localization pattern but did not have ITD c-KIT mutations. Results No mutations or polymorphisms were identified in exons 16–20 of any of the MCTs examined. Conclusion In conclusion, mutations in the phospho-transferase portion of c-KIT's kinase domain do not play an important role in the progression of canine cutaneous MCTs, or in the aberrant localization of KIT in canine MCTs. PMID:16579858

The DYT1 gene on 9q34 is responsible for most cases of early limb-onset idiopathic torsion dystonia in non-Jews

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kramer, P.L.; Heiman, G.A.; Leon, D. de

1994-09-01

Idiopathic torsion dystonia (ITD) is characterized by involuntary twisting movements and postures. A gene for this disorder, DYT1, was mapped to chromosome 9q34 in 12 Ashkenazi Jewish (AJ) families and one large non-Jewish kindred. In the AJ population, strong linkage disequilibrium exists between DYT1 and adjacent markers within a 2-cM region. The associated haplotype occurs in >90% of early limb-onset AJ cases. The authors examined seven non-Jewish ITD families of northern European and French Canadian descent to determine the extent to which early-onset ITD in non-Jews maps to DYT1. Results are consistent with linkage to the DYT1 region. Affected individualsmore » in these families are clinically similar to the AJ cases, i.e., the site of onset is predominantly in the limbs and at least one individual in each pedigree had onset before age 12 years. None carries the AJ haplotype; therefore, they probably represent different mutations in the DYT1 gene. The two French Canadian families, however, display the same haplotype. Estimates of penetrance in non-Jewish families range from .40 to .75. They identified disease gene carriers and, with adjustments for age at onset, obtained a direct estimate of penetrance of .46. This is consistent with estimates of 30%-40% in the AJ population. Two other non-Jewish families with atypical ITD (later onset and/or cranial or cervical involvement) are not linked to DYT1, which indicates involvement of other genes in dystonia. 26 refs., 1 fig., 3 tabs.« less

Enhancing interaural-delay-based extents of laterality at high frequencies by using ``transposed stimuli''

NASA Astrophysics Data System (ADS)

Bernstein, Leslie R.; Trahiotis, Constantine

2003-06-01

An acoustic pointing task was used to determine whether interaural temporal disparities (ITDs) conveyed by high-frequency ``transposed'' stimuli would produce larger extents of laterality than ITDs conveyed by bands of high-frequency Gaussian noise. The envelopes of transposed stimuli are designed to provide high-frequency channels with information similar to that conveyed by the waveforms of low-frequency stimuli. Lateralization was measured for low-frequency Gaussian noises, the same noises transposed to 4 kHz, and high-frequency Gaussian bands of noise centered at 4 kHz. Extents of laterality obtained with the transposed stimuli were greater than those obtained with bands of Gaussian noise centered at 4 kHz and, in some cases, were equivalent to those obtained with low-frequency stimuli. In a second experiment, the general effects on lateral position produced by imposed combinations of bandwidth, ITD, and interaural phase disparities (IPDs) on low-frequency stimuli remained when those stimuli were transposed to 4 kHz. Overall, the data were fairly well accounted for by a model that computes the cross-correlation subsequent to known stages of peripheral auditory processing augmented by low-pass filtering of the envelopes within the high-frequency channels of each ear.

Tympanic-response transition in ICE: Dependence upon the interaural cavity's shape

NASA Astrophysics Data System (ADS)

van Hemmen, J. Leo

More than half of the terrestrial vertebrates have internally coupled ears (ICE), where an interaural cavity of some shape acoustically couples the eardrums. Hence what the animal's auditory system perceives is not the outside stimulus but the superposition of outside and internal pressure on the two eardrums, resulting in so-called internal time and level difference, iTD and iLD, which are keys to sound localization. For a cylindrical shape, it is known that on the frequency axis two domains with appreciably increased iTD and iLD values occur, segregated by the eardrum's fundamental frequency. Here we analyze the case where, as in nature, two or more canals couple the eardrums so that, by opening one of the canals, the animal can switch from coupled to two independent ears. We analyze the iTD/iLD transition and its dependence upon the interaural cavity's size and shape. As compared to a single connection, the iTD performance is preserved to a large extent. Nonetheless, the price to pay for freedom of choice is a reduced frequency range with high-iTD plateau. Work done in collaboration with A.P. Vedurmudi; partially supported by BCCN-Munich.

Partonic quasidistributions of the proton and pion from transverse-momentum distributions

NASA Astrophysics Data System (ADS)

Broniowski, Wojciech; Arriola, Enrique Ruiz

2018-02-01

The parton quasidistribution functions (QDFs) of Ji have been found by Radyushkin to be directly related to the transverse momentum distributions (TMDs), to the pseudodistributions, and to the Ioffe-time distributions (ITDs). This makes the QDF results at finite longitudinal momentum of the hadron interesting in their own right. Moreover, the QDF-TMD relation provides a gateway to the pertinent QCD evolution, with respect to the resolution scale Q , for the QDFs. Using the Kwieciński evolution equations and well established parametrizations at a low initial scale, we analyze the QCD evolution of quark and gluon QDF components of the proton and the pion. We discuss the resulting breaking of the longitudinal-transverse factorization and show that it has little impact on QDFs at the relatively low scales presently accessible on the lattice, but the effect is visible in reduced ITDs at sufficiently large values of the Ioffe time. Sum rules involving derivatives of ITDs and moments of the parton distribution functions (PDFs) are applied to the European Twisted Mass Collaboration lattice data. This allows us for a lattice determination of the transverse-momentum width of the TMDs from QDF studies.

Slow Temporal Integration Enables Robust Neural Coding and Perception of a Cue to Sound Source Location.

PubMed

Brown, Andrew D; Tollin, Daniel J

2016-09-21

In mammals, localization of sound sources in azimuth depends on sensitivity to interaural differences in sound timing (ITD) and level (ILD). Paradoxically, while typical ILD-sensitive neurons of the auditory brainstem require millisecond synchrony of excitatory and inhibitory inputs for the encoding of ILDs, human and animal behavioral ILD sensitivity is robust to temporal stimulus degradations (e.g., interaural decorrelation due to reverberation), or, in humans, bilateral clinical device processing. Here we demonstrate that behavioral ILD sensitivity is only modestly degraded with even complete decorrelation of left- and right-ear signals, suggesting the existence of a highly integrative ILD-coding mechanism. Correspondingly, we find that a majority of auditory midbrain neurons in the central nucleus of the inferior colliculus (of chinchilla) effectively encode ILDs despite complete decorrelation of left- and right-ear signals. We show that such responses can be accounted for by relatively long windows of bilateral excitatory-inhibitory interaction, which we explicitly measure using trains of narrowband clicks. Neural and behavioral data are compared with the outputs of a simple model of ILD processing with a single free parameter, the duration of excitatory-inhibitory interaction. Behavioral, neural, and modeling data collectively suggest that ILD sensitivity depends on binaural integration of excitation and inhibition within a ≳3 ms temporal window, significantly longer than observed in lower brainstem neurons. This relatively slow integration potentiates a unique role for the ILD system in spatial hearing that may be of particular importance when informative ITD cues are unavailable. In mammalian hearing, interaural differences in the timing (ITD) and level (ILD) of impinging sounds carry critical information about source location. However, natural sounds are often decorrelated between the ears by reverberation and background noise, degrading the fidelity of both ITD and ILD cues. Here we demonstrate that behavioral ILD sensitivity (in humans) and neural ILD sensitivity (in single neurons of the chinchilla auditory midbrain) remain robust under stimulus conditions that render ITD cues undetectable. This result can be explained by "slow" temporal integration arising from several-millisecond-long windows of excitatory-inhibitory interaction evident in midbrain, but not brainstem, neurons. Such integrative coding can account for the preservation of ILD sensitivity despite even extreme temporal degradations in ecological acoustic stimuli. Copyright © 2016 the authors 0270-6474/16/369908-14$15.00/0.

Microcomputer-controlled world time display for public area viewing

NASA Astrophysics Data System (ADS)

Yep, S.; Rashidian, M.

1982-05-01

The design, development, and implementation of a microcomputer-controlled world clock is discussed. The system, designated international Time Display System (ITDS), integrates a Geochron Calendar Map and a microcomputer-based digital display to automatically compensate for daylight savings time, leap year, and time zone differences. An in-depth technical description of the design and development of the electronic hardware, firmware, and software systems is provided. Reference material on the time zones, fabrication techniques, and electronic subsystems are also provided.

A Systems Engineering Framework for Implementing a Security and Critical Patch Management Process in Diverse Environments (Academic Departments' Workstations)

NASA Astrophysics Data System (ADS)

Mohammadi, Hadi

Use of the Patch Vulnerability Management (PVM) process should be seriously considered for any networked computing system. The PVM process prevents the operating system (OS) and software applications from being attacked due to security vulnerabilities, which lead to system failures and critical data leakage. The purpose of this research is to create and design a Security and Critical Patch Management Process (SCPMP) framework based on Systems Engineering (SE) principles. This framework will assist Information Technology Department Staff (ITDS) to reduce IT operating time and costs and mitigate the risk of security and vulnerability attacks. Further, this study evaluates implementation of the SCPMP in the networked computing systems of an academic environment in order to: 1. Meet patch management requirements by applying SE principles. 2. Reduce the cost of IT operations and PVM cycles. 3. Improve the current PVM methodologies to prevent networked computing systems from becoming the targets of security vulnerability attacks. 4. Embed a Maintenance Optimization Tool (MOT) in the proposed framework. The MOT allows IT managers to make the most practicable choice of methods for deploying and installing released patches and vulnerability remediation. In recent years, there has been a variety of frameworks for security practices in every networked computing system to protect computer workstations from becoming compromised or vulnerable to security attacks, which can expose important information and critical data. I have developed a new mechanism for implementing PVM for maximizing security-vulnerability maintenance, protecting OS and software packages, and minimizing SCPMP cost. To increase computing system security in any diverse environment, particularly in academia, one must apply SCPMP. I propose an optimal maintenance policy that will allow ITDS to measure and estimate the variation of PVM cycles based on their department's requirements. My results demonstrate that MOT optimizes the process of implementing SCPMP in academic workstations.

Soil Moisture Estimation Using Hyperspectral SWIR Imagery

NASA Astrophysics Data System (ADS)

Lewis, D.

2007-12-01

The U.S. Geological Survey (USGS) is engaged with the U.S. Department of Agriculture's (USDA) Agricultural Research Service (ARS) and the University of Georgia's National Environmentally Sound Production Agriculture Laboratory (NESPAL) both in Tifton, Georgia, USA, to develop transformations for medium and high resolution remotely sensed images to generate moisture indicators for soil. The Institute for Technology Development (ITD) is located at the Stennis Space Center in southern Mississippi and has developed hyperspectral sensor systems that, when mounted in aircraft, collect electromagnetic reflectance data of the terrain. The sensor suite consists of sensors for three different sections of the electromagnetic spectrum; the Ultra-Violet (UV), Visible/Near InfraRed (VNIR) and Short Wave InfraRed (SWIR). The USDA/ ARS' Southeast Watershed Research Laboratory has probes that measure and record soil moisture. Data taken from the ITD SWIR sensor and the USDA/ARS soil moisture meters were analyzed to study the informatics relationships between SWIR data and measured soil moisture. The geographic locations of 29 soil moisture meters provided by the USDA/ARS are in the vicinity of Tifton, Georgia. Using USGS Digital Ortho Quads (DOQ), flightlines were drawn over the 29 soil moisture meters. The SWIR sensor was installed into an aircraft. The coordinates for the flightlines were also loaded into the navigational system of the aircraft. This airborne platform was used to collect the data over these flightlines. In order to prepare the data set for analysis, standard preprocessing was performed. These standard processes included sensor calibration, spectral subsetting, and atmospheric calibration. All 60 bands of the SWIR data were collected for each line in the image data, 15 bands of which were stripped from the data set leaving 45 bands of information in the wavelength range of 906 to 1705 nanometers. All the image files were calibrated using the regression equations generated by using radiometer data collected over calibration tarps. Regions of Interest (ROI) were drawn over the image data set corresponding with the location of the soil moisture meters. Scripts written in ENVI's Interactive Data Language (IDL) were developed to extract the spectra from each of the processed hyperspectral image data over each soil moisture meter from its corresponding ROI. The informatics relationship between soil moisture and SWIR spectra was identified by using the resulting data set.

Usefulness of BCOR gene mutation as a prognostic factor in acute myeloid leukemia with intermediate cytogenetic prognosis.

PubMed

Terada, Kazuki; Yamaguchi, Hiroki; Ueki, Toshimitsu; Usuki, Kensuke; Kobayashi, Yutaka; Tajika, Kenji; Gomi, Seiji; Kurosawa, Saiko; Saito, Riho; Furuta, Yutaka; Miyadera, Keiki; Tokura, Taichiro; Marumo, Atushi; Omori, Ikuko; Sakaguchi, Masahiro; Fujiwara, Yusuke; Yui, Shunsuke; Ryotokuji, Takeshi; Arai, Kunihito; Kitano, Tomoaki; Wakita, Satoshi; Fukuda, Takahiro; Inokuchi, Koiti

2018-04-16

BCOR gene is a transcription regulatory factor that plays an essential role in normal hematopoiesis. The wider introduction of next-generation sequencing technology has led to reports in recent years of mutations in the BCOR gene in acute myeloid leukemia (AML), but the related clinical characteristics and prognosis are not sufficiently understood. We investigated the clinical characteristics and prognosis of 377 de novo AML cases with BCOR or BCORL1 mutation. BCOR or BCORL1 gene mutations were found in 28 cases (7.4%). Among cases aged 65 years or below that were also FLT3-ITD-negative and in the intermediate cytogenetic prognosis group, BCOR or BCORL1 gene mutations were observed in 11% of cases (12 of 111 cases), and this group had significantly lower 5-year overall survival (OS) (13.6% vs. 55.0%, P=0.0021) and relapse-free survival (RFS) (14.3% vs. 44.5%, P=0.0168) compared to cases without BCOR or BCORL1 gene mutations. Multivariate analysis demonstrated that BCOR mutations were an independent unfavorable prognostic factor (P=0.0038, P=0.0463) for both OS and RFS. In cases of AML that are FLT3-ITD-negative, aged 65 years or below, and in the intermediate cytogenetic prognosis group, which are considered to have relatively favorable prognosis, BCOR gene mutations appear to be an important prognostic factor. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Security threats categories in healthcare information systems.

PubMed

Samy, Ganthan Narayana; Ahmad, Rabiah; Ismail, Zuraini

2010-09-01

This article attempts to investigate the various types of threats that exist in healthcare information systems (HIS). A study has been carried out in one of the government-supported hospitals in Malaysia.The hospital has been equipped with a Total Hospital Information System (THIS). The data collected were from three different departments, namely the Information Technology Department (ITD), the Medical Record Department (MRD), and the X-Ray Department, using in-depth structured interviews. The study identified 22 types of threats according to major threat categories based on ISO/IEC 27002 (ISO 27799:2008). The results show that the most critical threat for the THIS is power failure followed by acts of human error or failure and other technological factors. This research holds significant value in terms of providing a complete taxonomy of threat categories in HIS and also an important component in the risk analysis stage.

Evolution of the Sabin Vaccine into Pathogenic Derivatives without Appreciable Changes in Antigenic Properties: Need for Improvement of Current Poliovirus Surveillance▿

PubMed Central

Yakovenko, Maria L.; Korotkova, Ekaterina A.; Ivanova, Olga E.; Eremeeva, Tatyana P.; Samoilovich, Elena; Uhova, Iryna; Gavrilin, Gene V.; Agol, Vadim I.

2009-01-01

The Sabin oral polio vaccine (OPV) may evolve into pathogenic viruses, causing sporadic cases and outbreaks of poliomyelitis. Such vaccine-derived polioviruses (VDPV) generally exhibit altered antigenicity. The current paradigm to distinguish VDPV from OPV and wild polioviruses is to characterize primarily those poliovirus isolates that demonstrate deviations from OPV in antigenic and genetic intratypic differentiation (ITD) tests. Here we report on two independent cases of poliomyelitis caused by VDPVs with “Sabin-like” properties in several ITD assays. The results suggest the existence of diverse pathways of OPV evolution and necessitate improvement of poliovirus surveillance, which currently potentially misses this class of VDPV. PMID:19129444

Evolution of the Sabin vaccine into pathogenic derivatives without appreciable changes in antigenic properties: need for improvement of current poliovirus surveillance.

PubMed

Yakovenko, Maria L; Korotkova, Ekaterina A; Ivanova, Olga E; Eremeeva, Tatyana P; Samoilovich, Elena; Uhova, Iryna; Gavrilin, Gene V; Agol, Vadim I

2009-04-01

The Sabin oral polio vaccine (OPV) may evolve into pathogenic viruses, causing sporadic cases and outbreaks of poliomyelitis. Such vaccine-derived polioviruses (VDPV) generally exhibit altered antigenicity. The current paradigm to distinguish VDPV from OPV and wild polioviruses is to characterize primarily those poliovirus isolates that demonstrate deviations from OPV in antigenic and genetic intratypic differentiation (ITD) tests. Here we report on two independent cases of poliomyelitis caused by VDPVs with "Sabin-like" properties in several ITD assays. The results suggest the existence of diverse pathways of OPV evolution and necessitate improvement of poliovirus surveillance, which currently potentially misses this class of VDPV.

Changes in Arctic Sea Ice Floe Size Distribution in the Marginal Ice Zone in a Thickness and Floe Size Distribution Model

NASA Astrophysics Data System (ADS)

Zhang, J.; Stern, H. L., III; Hwang, P. B.; Schweiger, A. J. B.; Stark, M.; Steele, M.

2015-12-01

To better describe the state of sea ice in the marginal ice zone (MIZ) with floes of varying thicknesses and sizes, both an ice thickness distribution (ITD) and a floe size distribution (FSD) are needed. We have developed a FSD theory [Zhang et al., 2015] that is coupled to the ITD theory of Thorndike et al. [1975] in order to explicitly simulate the evolution of FSD and ITD jointly. The FSD theory includes a FSD function and a FSD conservation equation in parallel with the ITD equation. The FSD equation takes into account changes in FSD due to ice advection, thermodynamic growth, and lateral melting. It also includes changes in FSD because of mechanical redistribution of floe size due to ice opening, ridging and, particularly, ice fragmentation induced by stochastic ocean surface waves. The floe size redistribution due to ice fragmentation is based on the assumption that wave-induced breakup is a random process such that when an ice floe is broken, floes of any smaller sizes have an equal opportunity to form, without being either favored or excluded. It is also based on the assumption that floes of larger sizes are easier to break because they are subject to larger flexure-induced stresses and strains than smaller floes that are easier to ride with waves with little bending; larger floes also have higher areal coverages and therefore higher probabilities to break. These assumptions with corresponding formulations ensure that the simulated FSD follows a power law as observed by satellites and airborne surveys. The FSD theory has been tested in the Pan-arctic Ice/Ocean Modeling and Assimilation System (PIOMAS). The existing PIOMAS has 12 categories each for ice thickness, ice enthalpy, and snow depth. With the implementation of the FSD theory, PIOMAS is able to represent 12 categories of floe sizes ranging from 0.1 m to ~3000 m. It is found that the simulated 12-category FSD agrees reasonably well with FSD derived from SAR and MODIS images. In this study, we will examine PIOMAS-estimated variability and changes in Arctic FSD over the period 1979-present. Thorndike, A. S., D. A. Rothrock, G. A. Maykut, and R. Colony, The thickness distribution of sea ice. J. Geophys. Res., 80, 1975. Zhang, J., A. Schweiger, M. Steele, and H. Stern, Sea ice floe size distribution in the marginal ice zone: Theory and numerical experiments, J. Geophys. Res., 120, 2015.

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship.

PubMed

Liu, Tao; Ivaturi, Vijay; Sabato, Philip; Gobburu, Jogarao V S; Greer, Jacqueline M; Wright, John J; Smith, B Douglas; Pratz, Keith W; Rudek, Michelle A

2018-04-27

Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (E max ) model. Sorafenib could inhibit FLT3-ITD activity by 100% with an IC 50 of 69.3 ng/mL and ERK activity by 84% with an IC 50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure-response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3-ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Lateralization and Binaural Interaction of Middle-Latency and Late-Brainstem Components of the Auditory Evoked Response.

PubMed

Dykstra, Andrew R; Burchard, Daniel; Starzynski, Christian; Riedel, Helmut; Rupp, Andre; Gutschalk, Alexander

2016-08-01

We used magnetoencephalography to examine lateralization and binaural interaction of the middle-latency and late-brainstem components of the auditory evoked response (the MLR and SN10, respectively). Click stimuli were presented either monaurally, or binaurally with left- or right-leading interaural time differences (ITDs). While early MLR components, including the N19 and P30, were larger for monaural stimuli presented contralaterally (by approximately 30 and 36 % in the left and right hemispheres, respectively), later components, including the N40 and P50, were larger ipsilaterally. In contrast, MLRs elicited by binaural clicks with left- or right-leading ITDs did not differ. Depending on filter settings, weak binaural interaction could be observed as early as the P13 but was clearly much larger for later components, beginning at the P30, indicating some degree of binaural linearity up to early stages of cortical processing. The SN10, an obscure late-brainstem component, was observed consistently in individuals and showed linear binaural additivity. The results indicate that while the MLR is lateralized in response to monaural stimuli-and not ITDs-this lateralization reverses from primarily contralateral to primarily ipsilateral as early as 40 ms post stimulus and is never as large as that seen with fMRI.

Binaural hearing in children using Gaussian enveloped and transposed tones.

PubMed

Ehlers, Erica; Kan, Alan; Winn, Matthew B; Stoelb, Corey; Litovsky, Ruth Y

2016-04-01

Children who use bilateral cochlear implants (BiCIs) show significantly poorer sound localization skills than their normal hearing (NH) peers. This difference has been attributed, in part, to the fact that cochlear implants (CIs) do not faithfully transmit interaural time differences (ITDs) and interaural level differences (ILDs), which are known to be important cues for sound localization. Interestingly, little is known about binaural sensitivity in NH children, in particular, with stimuli that constrain acoustic cues in a manner representative of CI processing. In order to better understand and evaluate binaural hearing in children with BiCIs, the authors first undertook a study on binaural sensitivity in NH children ages 8-10, and in adults. Experiments evaluated sound discrimination and lateralization using ITD and ILD cues, for stimuli with robust envelope cues, but poor representation of temporal fine structure. Stimuli were spondaic words, Gaussian-enveloped tone pulse trains (100 pulse-per-second), and transposed tones. Results showed that discrimination thresholds in children were adult-like (15-389 μs for ITDs and 0.5-6.0 dB for ILDs). However, lateralization based on the same binaural cues showed higher variability than seen in adults. Results are discussed in the context of factors that may be responsible for poor representation of binaural cues in bilaterally implanted children.

Comparison of Interaural Electrode Pairing Methods for Bilateral Cochlear Implants

PubMed Central

Dietz, Mathias

2015-01-01

In patients with bilateral cochlear implants (CIs), pairing matched interaural electrodes and stimulating them with the same frequency band is expected to facilitate binaural functions such as binaural fusion, localization, and spatial release from masking. Because clinical procedures typically do not include patient-specific interaural electrode pairing, it remains the case that each electrode is allocated to a generic frequency range, based simply on the electrode number. Two psychoacoustic techniques for determining interaurally paired electrodes have been demonstrated in several studies: interaural pitch comparison and interaural time difference (ITD) sensitivity. However, these two methods are rarely, if ever, compared directly. A third, more objective method is to assess the amplitude of the binaural interaction component (BIC) derived from electrically evoked auditory brainstem responses for different electrode pairings; a method has been demonstrated to be a potential candidate for bilateral CI users. Here, we tested all three measures in the same eight CI users. We found good correspondence between the electrode pair producing the largest BIC and the electrode pair producing the maximum ITD sensitivity. The correspondence between the pairs producing the largest BIC and the pitch-matched electrode pairs was considerably weaker, supporting the previously proposed hypothesis that whilst place pitch might adapt over time to accommodate mismatched inputs, sensitivity to ITDs does not adapt to the same degree. PMID:26631108

The outcome of allogeneic hematopoietic cell transplantation for children with FMS-like tyrosine kinase 3 internal tandem duplication-positive acute myelogenous leukemia.

PubMed

Schechter, Tal; Gassas, Adam; Chen, Heidi; Pollard, Jessica; Meshinchi, Soheil; Zaidman, Irina; Hitzler, Johann; Abdelhaleem, Mohamed; Ho, Richard; Domm, Jennifer; Woolfrey, Ann; Frangoul, Haydar

2015-01-01

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is a somatic mutation associated with poor outcome when treated with chemotherapy alone. In children, hematopoietic stem cell transplantation (HSCT) is recommended, but very limited data on outcome are reported. We determined the outcome of 29 children with FLT3/ITD-positive acute myelogenous leukemia (AML) who underwent allogeneic HSCT in 4 pediatric centers. Eleven patients (38%) received matched related donor hematopoietic stem cells and 18 (62%) received alternative donors. Eighteen patients (62%) received total body irradiation (TBI)-based regimens. No patients experienced transplantation-related mortality. Eleven patients (38%) experienced relapsed disease. The cumulative incidence of relapse at 2 years was 34.7% (95% confidence interval [CI], 20.4% to 54.9%). Two-year disease-free survival (DFS) and overall survival (OS) were 65.3% (95% CI, 45.1% to 79.6%) and 82.2% (95% CI, 58.5% to 91.3%), respectively. There was no difference in the DFS of patients who received transplants from related donors versus the DFS of those who received transplants from alternative donors (hazard ratio [HR], 2.64; 95% CI, .79 to 8.76; P = .10), using univariate analysis. Patients with higher FLT3/ITD ratio at diagnosis had significantly worse DFS (HR, 1.42; 95% CI, 1.04 to 1.93; P = .03). The use of TBI in the preparative regimen was associated with superior DFS (HR, .29; 95% CI, .08 to .99; P = .04) and OS (HR, .07; 95% CI, .01 to .62; P = .002). We conclude that allogeneic HSCT improves DFS and OS in children with FLT3/ITD-positive AML compared with what has been reported in those treated with chemotherapy alone. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Clinical and hemodynamic comparison of 15:2 and 30:2 compression-to-ventilation ratios for cardiopulmonary resuscitation.

PubMed

Yannopoulos, Demetris; Aufderheide, Tom P; Gabrielli, Andrea; Beiser, David G; McKnite, Scott H; Pirrallo, Ronald G; Wigginton, Jane; Becker, Lance; Vanden Hoek, Terry; Tang, Wanchun; Nadkarni, Vinay M; Klein, John P; Idris, Ahamed H; Lurie, Keith G

2006-05-01

To compare cardiopulmonary resuscitation (CPR) with a compression to ventilation (C:V) ratio of 15:2 vs. 30:2, with and without use of an impedance threshold device (ITD). Prospective randomized animal and manikin study. Animal laboratory and emergency medical technician training facilities. Twenty female pigs and 20 Basic Life Support (BLS)-certified rescuers. Acid-base status, cerebral, and cardiovascular hemodynamics were evaluated in 18 pigs in cardiac arrest randomized to a C:V ratio of 15:2 or 30:2. After 6 mins of cardiac arrest and 6 mins of CPR, an ITD was added. Compared to 15:2, 30:2 significantly increased diastolic blood pressure (20 +/- 1 to 26 +/- 1; p < .01); coronary perfusion pressure (18 +/- 1 to 25 +/- 2; p = .04); cerebral perfusion pressure (16 +/- 3 to 18 +/- 3; p = .07); common carotid blood flow (48 +/- 5 to 82 +/- 5 mL/min; p < .001); end-tidal CO2 (7.7 +/- 0.9 to 15.7 +/- 2.4; p < .0001); and mixed venous oxygen saturation (26 +/- 5 to 36 +/- 5, p < .05). Hemodynamics improved further with the ITD. Oxygenation and arterial pH were similar. Only one of nine pigs had return of spontaneous circulation with 15:2, vs. six of nine with 30:2 (p < 0.03). HUMANS: Fatigue and quality of CPR performance were evaluated in 20 BLS-certified rescuers randomized to perform CPR for 5 mins at 15:2 or 30:2 on a recording CPR manikin. There were no significant differences in the quality of CPR performance or measurement of fatigue. Significantly more compressions per minute were delivered with 30:2 in both the animal and human studies. These data strongly support the contention that a ratio of 30:2 is superior to 15:2 during manual CPR and that the ITD further enhances circulation with both C:V ratios.

Toward an Ultralow-Power Onboard Processor for Tongue Drive System

PubMed Central

Viseh, Sina; Ghovanloo, Maysam; Mohsenin, Tinoosh

2015-01-01

The Tongue Drive System (TDS) is a new unobtrusive, wireless, and wearable assistive device that allows for real-time tracking of the voluntary tongue motion in the oral space for communication, control, and navigation applications. The latest TDS prototype appears as a wireless headphone and has been tested in human subject trials. However, the robustness of the external TDS (eTDS) in real-life outdoor conditions may not meet safety regulations because of the limited mechanical stability of the headset. The intraoral TDS (iTDS), which is in the shape of a dental retainer, firmly clasps to the upper teeth and resists sensor misplacement. However, the iTDS has more restrictions on its dimensions, limiting the battery size and consequently requiring a considerable reduction in its power consumption to operate over an extended period of two days on a single charge. In this brief, we propose an ultralow-power local processor for the TDS that performs all signal processing on the transmitter side, following the sensors. Assuming the TDS user on average issuing one command/s, implementing the computational engine reduces the data volume that needs to be wirelessly transmitted to a PC or smartphone by a factor of 1500×, from 12 kb/s to ~8 b/s. The proposed design is implemented on an ultralow-power IGLOO nano field-programmable gate array (FPGA) and is tested on AGLN250 prototype board. According to our post-place-and-route results, implementing the engine on the FPGA significantly drops the required data transmission, while an application-specific integrated circuit (ASIC) implementation in a 65-nm CMOS results in a 15× power saving compared to the FPGA solution and occupies a 0.02-mm2 footprint. As a result, the power consumption and size of the iTDS will be significantly reduced through the use of a much smaller rechargeable battery. Moreover, the system can operate longer following every recharge, improving the iTDS usability. PMID:26185489

Toward an Ultralow-Power Onboard Processor for Tongue Drive System.

PubMed

Viseh, Sina; Ghovanloo, Maysam; Mohsenin, Tinoosh

2015-02-01

The Tongue Drive System (TDS) is a new unobtrusive, wireless, and wearable assistive device that allows for real-time tracking of the voluntary tongue motion in the oral space for communication, control, and navigation applications. The latest TDS prototype appears as a wireless headphone and has been tested in human subject trials. However, the robustness of the external TDS (eTDS) in real-life outdoor conditions may not meet safety regulations because of the limited mechanical stability of the headset. The intraoral TDS (iTDS), which is in the shape of a dental retainer, firmly clasps to the upper teeth and resists sensor misplacement. However, the iTDS has more restrictions on its dimensions, limiting the battery size and consequently requiring a considerable reduction in its power consumption to operate over an extended period of two days on a single charge. In this brief, we propose an ultralow-power local processor for the TDS that performs all signal processing on the transmitter side, following the sensors. Assuming the TDS user on average issuing one command/s, implementing the computational engine reduces the data volume that needs to be wirelessly transmitted to a PC or smartphone by a factor of 1500×, from 12 kb/s to ~8 b/s. The proposed design is implemented on an ultralow-power IGLOO nano field-programmable gate array (FPGA) and is tested on AGLN250 prototype board. According to our post-place-and-route results, implementing the engine on the FPGA significantly drops the required data transmission, while an application-specific integrated circuit (ASIC) implementation in a 65-nm CMOS results in a 15× power saving compared to the FPGA solution and occupies a 0.02-mm 2 footprint. As a result, the power consumption and size of the iTDS will be significantly reduced through the use of a much smaller rechargeable battery. Moreover, the system can operate longer following every recharge, improving the iTDS usability.

Effect of 3 Different Doses of Intrathecal Dexmedetomidine (2.5µg, 5µg, and 10 µg) on Subarachnoid Block Characteristics: A Prospective Randomized Double Blind Dose-Response Trial.

PubMed

Gupta, Mayank; Gupta, Priyanka; Singh, Dhananjay Kumar

2016-03-01

The extended analgesic efficacy of intrathecal dexmedetomidine (ITD) has been investigated in a few clinical trials; however, there is a lack of conclusive evidence upon its ideal dosage. To elucidate the dose-response relationship between ITD and subarachnoid block characteristics, particularly the duration of analgesia and differential analgesia (DA: defined as time difference from the offset of motor blockade to the first analgesic requirement on numerical rating scale = 4.0). Prospective, randomized double blind active control trial. Medical college teaching hospital. Ninety adult (18 - 60 years) patients undergoing elective lower abdominal and lower limb surgeries were randomized into 3 groups to receive intrathecal 0.5% bupivacaine 3 mL with 2.5 µg (group BD2.5), 5µg (group BD5), or 10 µg (group BD10) dexmedetomidine in 0.5 mL normal saline. The 2 segment sensory regression times (TSSRT), duration of motor blockade analgesia, DA, and perioperative adverse effects were assessed. The primary outcome was duration of analgesia and DA. ANOVA, Kruskal Wallis test, Chi-square (x2), and Fisher's exact test, significance: P < 0.05. The onset of sensory block was significantly earlier in group BD10 compared with group BD5 (P = 0.035) and BD2.5 (P = 0.010) while the onset of motor block was significantly earlier in group BD10 compared with BD2.5 (P = 0.020). There was a significant and dose-dependent prolongation of the duration of sensory block (127.50, 149.17, and 187.50 minutes; P < 0.001), motor block (258.50, 331, and 365 minutes; P < 0.001), analgesia (306.17, 396.50, and 512 minutes; P < 0.001), and DA (47.67, 65.50, and147 minutes; P < 0.001) with escalating doses of ITD, respectively. Group BD10 required significantly fewer rescue analgesics compared with other 2 groups (P = 0.001). Except for mild sedation which was significantly higher in group BD10; all the groups were comparable with respect to hemodynamic and other adverse effects. Lack of placebo group, exclusion of higher doses (15µg) of ITD, and short duration of postoperative follow-up. The addition of 10 µg compared with 2.5 µg or 5µg ITD to 0.5% hyperbaric bupivacaine is associated with significantly earlier onset of sensory and motor block as well as prolonged duration of sensory block, motor block, analgesia, and DA with a comparable adverse effect profile.

Comparison of various treatment modalities for acute tinnitus.

PubMed

Shim, Hyun Joon; Song, Seong Jun; Choi, A Young; Hyung Lee, Rae; Yoon, Sang Won

2011-12-01

Because in most cases the development of tinnitus is triggered by cochlear damage, there exists the opportunity to eliminate tinnitus while the cochlear lesion is still reversible. Therefore, we evaluated the therapeutic effects of various treatment modalities on acute subjective idiopathic tinnitus (SIT) and investigated prognostic factors affecting the treatment outcome. Prospective, controlled, double-blind trial. A total 107 patients who underwent treatment for unilateral SIT that had developed within the previous 3 months completed the study. The patients were randomly assigned into three groups according to the treatment modality: group I (n = 32), alprazolam orally for 3 months; group II (n = 35), as for group I plus four intratympanic dexamethasone (ITD) injections; and group III (n = 40), as for group II plus four intravenous injections of lipo-prostaglandin E(1) . The improvement rate of group II (75.8%) was significantly higher than that of group I (40.3%; P < .05), and there was no significant difference in the improvement rate of group III (50.0%) compared with groups I and II (P > .05). The cure rates of group II (25.8%) and group III (20.0%) were significantly higher than that of group I (9.8%; P < .05). There was a significant correlation between the cure rate and duration of symptoms. The results of the present study indicate that ITD injection plus alprazolam medication is the best treatment choice for acute SIT within 3 months of development. Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.

FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions.

PubMed

Larrosa-Garcia, Maria; Baer, Maria R

2017-06-01

The receptor tyrosine kinase fms -like tyrosine kinase 3 (FLT3), involved in regulating survival, proliferation, and differentiation of hematopoietic stem/progenitor cells, is expressed on acute myeloid leukemia (AML) cells in most patients. Mutations of FLT3 resulting in constitutive signaling are common in AML, including internal tandem duplication (ITD) in the juxtamembrane domain in 25% of patients and point mutations in the tyrosine kinase domain in 5%. Patients with AML with FLT3-ITD have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant. A number of inhibitors of FLT3 signaling have been identified and are in clinical trials, both alone and with chemotherapy, with the goal of improving clinical outcomes in patients with AML with FLT3 mutations. While inhibitor monotherapy produces clinical responses, they are usually incomplete and transient, and resistance develops rapidly. Diverse combination therapies have been suggested to potentiate the efficacy of FLT3 inhibitors and to prevent development of resistance or overcome resistance. Combinations with epigenetic therapies, proteasome inhibitors, downstream kinase inhibitors, phosphatase activators, and other drugs that alter signaling are being explored. This review summarizes the current status of translational and clinical research on FLT3 inhibitors in AML, and discusses novel combination approaches. Mol Cancer Ther; 16(6); 991-1001. ©2017 AACR . ©2017 American Association for Cancer Research.

Localization by interaural time difference (ITD): Effects of interaural frequency mismatch

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bonham, B.H.; Lewis, E.R.

1999-07-01

A commonly accepted physiological model for lateralization of low-frequency sounds by interaural time delay (ITD) stipulates that binaural comparison neurons receive input from frequency-matched channels from each ear. Here, the effects of hypothetical interaural frequency mismatches on this model are reported. For this study, the cat{close_quote}s auditory system peripheral to the binaural comparison neurons was represented by a neurophysiologically derived model, and binaural comparison neurons were represented by cross-correlators. The results of the study indicate that, for binaural comparison neurons receiving input from one cochlear channel from each ear, interaural CF mismatches may serve to either augment or diminish themore » effective difference in ipsilateral and contralateral axonal time delays from the periphery to the binaural comparison neuron. The magnitude of this increase or decrease in the effective time delay difference can be up to 400 {mu}s for CF mismatches of 0.2 octaves or less for binaural neurons with CFs between 250 Hz and 2.5 kHz. For binaural comparison neurons with nominal CFs near 500 Hz, the 25-{mu}s effective time delay difference caused by a 0.012-octave CF mismatch is equal to the ITD previously shown to be behaviorally sufficient for the cat to lateralize a low-frequency sound source. {copyright} {ital 1999 Acoustical Society of America.}« less

Characteristics of stereo reproduction with parametric loudspeakers

NASA Astrophysics Data System (ADS)

Aoki, Shigeaki; Toba, Masayoshi; Tsujita, Norihisa

2012-05-01

A parametric loudspeaker utilizes nonlinearity of a medium and is known as a super-directivity loudspeaker. The parametric loudspeaker is one of the prominent applications of nonlinear ultrasonics. So far, the applications have been limited monaural reproduction sound system for public address in museum, station and street etc. In this paper, we discussed characteristics of stereo reproduction with two parametric loudspeakers by comparing with those with two ordinary dynamic loudspeakers. In subjective tests, three typical listening positions were selected to investigate the possibility of correct sound localization in a wide listening area. The binaural information was ILD (Interaural Level Difference) or ITD (Interaural Time Delay). The parametric loudspeaker was an equilateral hexagon. The inner and outer diameters were 99 and 112 mm, respectively. Signals were 500 Hz, 1 kHz, 2 kHz and 4 kHz pure tones and pink noise. Three young males listened to test signals 10 times in each listening condition. Subjective test results showed that listeners at the three typical listening positions perceived correct sound localization of all signals using the parametric loudspeakers. It was almost similar to those using the ordinary dynamic loudspeakers, however, except for the case of sinusoidal waves with ITD. It was determined the parametric loudspeaker could exclude the contradiction between the binaural information ILD and ITD that occurred in stereo reproduction with ordinary dynamic loudspeakers because the super directivity of parametric loudspeaker suppressed the cross talk components.

Mechanisms for Adjusting Interaural Time Differences to Achieve Binaural Coincidence Detection

PubMed Central

Seidl, Armin H.; Rubel, Edwin W; Harris, David M.

2010-01-01

Understanding binaural perception requires detailed analyses of the neural circuitry responsible for the computation of interaural time differences (ITDs). In the avian brainstem, this circuit consists of internal axonal delay lines innervating an array of coincidence detector neurons that encode external ITDs. Nucleus magnocellularis (NM) neurons project to the dorsal dendritic field of the ipsilateral nucleus laminaris (NL) and to the ventral field of the contralateral NL. Contralateral-projecting axons form a delay line system along a band of NL neurons. Binaural acoustic signals in the form of phase-locked action potentials from NM cells arrive at NL and establish a topographic map of sound source location along the azimuth. These pathways are assumed to represent a circuit similar to the Jeffress model of sound localization, establishing a place code along an isofrequency contour of NL. Three-dimensional measurements of axon lengths reveal major discrepancies with the current model; the temporal offset based on conduction length alone makes encoding of physiological ITDs impossible. However, axon diameter and distances between Nodes of Ranvier also influence signal propagation times along an axon. Our measurements of these parameters reveal that diameter and internode distance can compensate for the temporal offset inferred from axon lengths alone. Together with other recent studies these unexpected results should inspire new thinking on the cellular biology, evolution and plasticity of the circuitry underlying low frequency sound localization in both birds and mammals. PMID:20053889

Extinction of auditory stimuli in hemineglect: Space versus ear.

PubMed

Spierer, Lucas; Meuli, Reto; Clarke, Stephanie

2007-02-01

Unilateral extinction of auditory stimuli, a key feature of the neglect syndrome, was investigated in 15 patients with right (11), left (3) or bilateral (1) hemispheric lesions using a verbal dichotic condition, in which each ear received simultaneously one word, and a interaural-time-difference (ITD) diotic condition, in which both ears received both words lateralised by means of ITD. Additional investigations included sound localisation, visuo-spatial attention and general cognitive status. Five patients presented a significant asymmetry in the ITD diotic test, due to a decrease of left hemispace reporting but no asymmetry was found in dichotic listening. Six other patients presented a significant asymmetry in the dichotic test due to a significant decrease of left or right ear reporting, but no asymmetry in diotic listening. Ten of the above patients presented mild to severe deficits in sound localisation and eight signs of visuo-spatial neglect (three with selective asymmetry in the diotic and five in the dichotic task). Four other patients presented a significant asymmetry in both the diotic and dichotic listening tasks. Three of them presented moderate deficits in localisation and all four moderate visuo-spatial neglect. Thus, extinction for left ear and left hemispace can double dissociate, suggesting distinct underlying neural processes. Furthermore, the co-occurrence with sound localisation disturbance and with visuo-spatial hemineglect speaks in favour of the involvement of multisensory attentional representations.

Aging effects on the Binaural Interaction Component of the Auditory Brainstem Response in the Mongolian Gerbil: Effects of Interaural Time and Level Differences

PubMed Central

Laumen, Geneviève; Tollin, Daniel J.; Beutelmann, Rainer; Klump, Georg M.

2016-01-01

The effect of interaural time difference (ITD) and interaural level difference (ILD) on wave 4 of the binaural and summed monaural auditory brainstem responses (ABRs) as well as on the DN1 component of the binaural interaction component (BIC) of the ABR in young and old Mongolian gerbils (Meriones unguiculatus) was investigated. Measurements were made at a fixed sound pressure level (SPL) and a fixed level above visually detected ABR threshold to compensate for individual hearing threshold differences. In both stimulation modes (fixed SPL and fixed level above visually detected ABR threshold) an effect of ITD on the latency and the amplitude of wave 4 as well as of the BIC was observed. With increasing absolute ITD values BIC latencies were increased and amplitudes were decreased. ILD had a much smaller effect on these measures. Old animals showed a reduced amplitude of the DN1 component. This difference was due to a smaller wave 4 in the summed monaural ABRs of old animals compared to young animals whereas wave 4 in the binaural-evoked ABR showed no age-related difference. In old animals the small amplitude of the DN1 component was correlated with small binaural-evoked wave 1 and wave 3 amplitudes. This suggests that the reduced peripheral input affects central binaural processing which is reflected in the BIC. PMID:27173973

Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment

PubMed Central

Jin, Linhua; Tabe, Yoko; Lu, Hongbo; Borthakur, Gautam; Miida, Takashi; Kantarjian, Hagop; Andreeff, Michael; Konopleva, Marina

2013-01-01

We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches. PMID:23036488

Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment.

PubMed

Jin, Linhua; Tabe, Yoko; Lu, Hongbo; Borthakur, Gautam; Miida, Takashi; Kantarjian, Hagop; Andreeff, Michael; Konopleva, Marina

2013-02-01

We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches. Copyright © 2012 Elsevier Ltd. All rights reserved.

Linkage analysis with chromosome 9 markers in hereditary essential tremor.

PubMed

Conway, D; Bain, P G; Warner, T T; Davis, M B; Findley, L J; Thompson, P D; Marsden, C D; Harding, A E

1993-07-01

Hereditary essential tremor (ET) is an autosomal dominant disorder with variable expression and reduced penetrance. A tremor indistinguishable from ET may be observed in patients with autosomal dominant idiopathic torsion dystonia (ITD), in which the disease locus has been mapped to 9q32-34 in some kindreds, tightly linked to the argininosuccinate synthetase (ASS) locus. We performed linkage analysis in 15 families with ET containing 60 definitely affected individuals, using dinucleotide repeat polymorphisms at the ASS locus and the Abelson locus (ABL). Cumulative lod scores were -19.5 for ASS and -10.8 for ABL at a recombination fraction of 0.01, and tight linkage to ASS was excluded individually in 11 of the families. These data indicate that the ET gene is not allelic to that causing ITD.

Speech-on-speech masking in a front-back dimension and analysis of binaural parameters in rooms using MLS methods

NASA Astrophysics Data System (ADS)

Aaronson, Neil L.

This dissertation deals with questions important to the problem of human sound source localization in rooms, starting with perceptual studies and moving on to physical measurements made in rooms. In Chapter 1, a perceptual study is performed relevant to a specific phenomenon the effect of speech reflections occurring in the front-back dimension and the ability of humans to segregate that from unreflected speech. Distracters were presented from the same source as the target speech, a loudspeaker directly in front of the listener, and also from a loudspeaker directly behind the listener, delayed relative to the front loudspeaker. Steps were taken to minimize the contributions of binaural difference cues. For all delays within +/-32 ms, a release from informational masking of about 2 dB occurred. This suggested that human listeners are able to segregate speech sources based on spatial cues, even with minimal binaural cues. In moving on to physical measurements in rooms, a method was sought for simultaneous measurement of room characteristics such as impulse response (IR) and reverberation time (RT60), and binaural parameters such as interaural time difference (ITD), interaural level difference (ILD), and the interaural cross-correlation function and coherence. Chapter 2 involves investigations into the usefulness of maximum length sequences (MLS) for these purposes. Comparisons to random telegraph noise (RTN) show that MLS performs better in the measurement of stationary and room transfer functions, IR, and RT60 by an order of magnitude in RMS percent error, even after Wiener filtering and exponential time-domain filtering have improved the accuracy of RTN measurements. Measurements were taken in real rooms in an effort to understand how the reverberant characteristics of rooms affect binaural parameters important to sound source localization. Chapter 3 deals with interaural coherence, a parameter important for localization and perception of auditory source width. MLS were used to measure waveform and envelope coherences in two rooms for various source distances and 0° azimuth through a head-and-torso simulator (KEMAR). A relationship is sought that relates these two types of coherence, since envelope coherence, while an important quantity, is generally less accessible than waveform coherence. A power law relationship is shown to exist between the two that works well within and across bands, for any source distance, and is robust to reverberant conditions of the room. Measurements of ITD, ILD, and coherence in rooms give insight into the way rooms affect these parameters, and in turn, the ability of listeners to localize sounds in rooms. Such measurements, along with room properties, are made and analyzed using MLS methods in Chapter 4. It was found that the pinnae cause incoherence for sound sources incident between 30° and 90°. In human listeners, this does not seem to adversely affect performance in lateralization experiments. The cause of poor coherence in rooms was studied as part of Chapter 4 as well. It was found that rooms affect coherence by introducing variance into the ITD spectra within the bands in which it is measured. A mathematical model to predict the interaural coherence within a band given the standard deviation of the ITD spectrum and the center frequency of the band gives an exponential relationship. This is found to work well in predicting measured coherence given ITD spectrum variance. The pinnae seem to affect the ITD spectrum in a similar way at incident sound angles for which coherence is poor in an anechoic environment.

The Development of a Remote Sensor System and Decision Support Systems Architecture to Monitor Resistance Development in Transgenic Crops

NASA Technical Reports Server (NTRS)

Cacas, Joseph; Glaser, John; Copenhaver, Kenneth; May, George; Stephens, Karen

2008-01-01

The United States Environmental Protection Agency (EPA) has declared that "significant benefits accrue to growers, the public, and the environment" from the use of transgenic pesticidal crops due to reductions in pesticide usage for crop pest management. Large increases in the global use of transgenic pesticidal crops has reduced the amounts of broad spectrum pesticides used to manage pest populations, improved yield and reduced the environmental impact of crop management. A significant threat to the continued use of this technology is the evolution of resistance in insect pest populations to the insecticidal Bt toxins expressed by the plants. Management of transgenic pesticidal crops with an emphasis on conservation of Bt toxicity in field populations of insect pests is important to the future of sustainable agriculture. A vital component of this transgenic pesticidal crop management is establishing the proof of concept basic understanding, situational awareness, and monitoring and decision support system tools for more than 133650 square kilometers (33 million acres) of bio-engineered corn and cotton for development of insect resistance . Early and recent joint NASA, US EPA and ITD remote imagery flights and ground based field experiments have provided very promising research results that will potentially address future requirements for crop management capabilities.

Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission.

PubMed

Brunner, Andrew M; Li, Shuli; Fathi, Amir T; Wadleigh, Martha; Ho, Vincent T; Collier, Kerry; Connolly, Christine; Ballen, Karen K; Cutler, Corey S; Dey, Bimalangshu R; El-Jawahri, Areej; Nikiforow, Sarah; McAfee, Steven L; Koreth, John; Deangelo, Daniel J; Alyea, Edwin P; Antin, Joseph H; Spitzer, Thomas R; Stone, Richard M; Soiffer, Robert J; Chen, Yi-Bin

2016-11-01

We performed a retrospective study analysing the effect of sorafenib, an oral fms-Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3-ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post-HCT initiation of sorafenib (yes/no) was evaluated as a time-varying covariate in the overall survival/progression-free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation. We identified 26 sorafenib patients and 55 controls. Median follow-up was 27·2 months post-HCT for sorafenib survivors, and 38·4 months for controls (P = 0·021). The median time to initiating sorafenib was 68 days post-HCT; 43 controls were alive without relapse at this cut-off. Sorafenib patients had improved 2-year OS in the d+68 landmark analysis (81% vs. 62%, P = 0·029). Sorafenib was associated with improved 2-year PFS (82% vs. 53%, P = 0·0081) and lower 2-year cumulative incidence of relapse (8·2% vs. 37·7%, P = 0·0077). In multivariate analysis, sorafenib significantly improved OS [Hazard ratio (HR) 0·26, P = 0·021] and PFS (HR 0·25, P = 0·016). There was no difference in 2-year non-relapse mortality (9·8% vs. 9·3%, P = 0·82) or 1-year chronic graft-versus-host disease (55·5% vs. 37·2%, P = 0·28). These findings suggest potential benefit of post-HCT sorafenib in FLT3-ITD AML, and support further evaluation of post-HCT FLT3 inhibition. © 2016 John Wiley & Sons Ltd.

FLT3 mutation and expression did not adversely affect clinical outcome of childhood acute leukaemia: a study of 531 Southeast Asian children by the Ma-Spore study group.

PubMed

Leow, Shuangjie; Kham, Shirley Kow-Yin; Ariffin, Hany; Quah, Thuan Chong; Yeoh, Allen Eng-Juh

2011-12-01

FMS-like tyrosine kinase 3 (FLT3) is critical for normal haematopoiesis and have been reported to be expressed in the majority of acute myeloid and lymphoid malignancies. We correlated the impact of FLT3 mutations and its expression with age, WHO 2008 classification and treatment outcome in 531 childhood acute leukaemias. Of 150 acute myeloid leukaemia (AMLs), 18 (12%) harboured FLT3-ITD while nine (6%) had FLT3-TKD. FLT3-ITD and -TKD were rare in acute megakaryoblastic leukaemia (AMKL; FLT3-ITD 0/26, FLT3-TKD 1/26) and children below 3 years (n = 2/48). Acute promyelocytic leukaemia (APL) with t(15;17);PML-RARα (n = 7/18; 39%) harboured the highest frequency of FLT3 mutations, followed by myelomonocytic (n = 4/18; 22%) and AML with t(8;21);RUNX1-RUNX1T1 (n = 2/21; 9%). FLT3 expression levels were also lowest in AMKL, both in Down's and non-Down's (p = 0.002) followed by patients <3 years (p = 0.001). The rarity of FLT3 mutations and expression levels in AMKL were independent of age. Conversely, only 2% of childhood acute lymphoblastic leukaemia (ALL) harboured FLT3 mutations (ITD = 1/381; TKD = 6/381). FLT3 was highly expressed in hyperdiploid ALL (p < 0.001). Of the 121 AMLs with clinical history, there were no significant differences in 4-year event-free survival (EFS) (46% vs. 38%; p = 0.46) and overall-survival (OS) (55% vs. 43%; p = 0.30) between FLT3-wildtype and ITD+ patients. Similarly, FLT3 expression levels did not influence survival in AML in both the good risk and non-good risk subgroups. FLT3 does not appear to be involved in the pathogenesis of AMKL, both in Down's and non-Down's. Therapeutic targets using FLT3 inhibitors may not be useful in AMKL and in young children with AML. Copyright © 2011 John Wiley & Sons, Ltd.

CRISPR/Cas9 gene drives in genetically variable and nonrandomly mating wild populations

PubMed Central

Drury, Douglas W.; Dapper, Amy L.; Siniard, Dylan J.; Zentner, Gabriel E.; Wade, Michael J.

2017-01-01

Synthetic gene drives based on CRISPR/Cas9 have the potential to control, alter, or suppress populations of crop pests and disease vectors, but it is unclear how they will function in wild populations. Using genetic data from four populations of the flour beetle Tribolium castaneum, we show that most populations harbor genetic variants in Cas9 target sites, some of which would render them immune to drive (ITD). We show that even a rare ITD allele can reduce or eliminate the efficacy of a CRISPR/Cas9-based synthetic gene drive. This effect is equivalent to and accentuated by mild inbreeding, which is a characteristic of many disease-vectoring arthropods. We conclude that designing such drives will require characterization of genetic variability and the mating system within and among targeted populations. PMID:28560324

Computation of interaural time difference in the owl's coincidence detector neurons.

PubMed

Funabiki, Kazuo; Ashida, Go; Konishi, Masakazu

2011-10-26

Both the mammalian and avian auditory systems localize sound sources by computing the interaural time difference (ITD) with submillisecond accuracy. The neural circuits for this computation in birds consist of axonal delay lines and coincidence detector neurons. Here, we report the first in vivo intracellular recordings from coincidence detectors in the nucleus laminaris of barn owls. Binaural tonal stimuli induced sustained depolarizations (DC) and oscillating potentials whose waveforms reflected the stimulus. The amplitude of this sound analog potential (SAP) varied with ITD, whereas DC potentials did not. The amplitude of the SAP was correlated with firing rate in a linear fashion. Spike shape, synaptic noise, the amplitude of SAP, and responsiveness to current pulses differed between cells at different frequencies, suggesting an optimization strategy for sensing sound signals in neurons tuned to different frequencies.

CRISPR/Cas9 gene drives in genetically variable and nonrandomly mating wild populations.

PubMed

Drury, Douglas W; Dapper, Amy L; Siniard, Dylan J; Zentner, Gabriel E; Wade, Michael J

2017-05-01

Synthetic gene drives based on CRISPR/Cas9 have the potential to control, alter, or suppress populations of crop pests and disease vectors, but it is unclear how they will function in wild populations. Using genetic data from four populations of the flour beetle Tribolium castaneum , we show that most populations harbor genetic variants in Cas9 target sites, some of which would render them immune to drive (ITD). We show that even a rare ITD allele can reduce or eliminate the efficacy of a CRISPR/Cas9-based synthetic gene drive. This effect is equivalent to and accentuated by mild inbreeding, which is a characteristic of many disease-vectoring arthropods. We conclude that designing such drives will require characterization of genetic variability and the mating system within and among targeted populations.

HGNET-BCOR Tumors of the Cerebellum: Clinicopathologic and Molecular Characterization of 3 Cases.

PubMed

Appay, Romain; Macagno, Nicolas; Padovani, Laetitia; Korshunov, Andrey; Kool, Marcel; André, Nicolas; Scavarda, Didier; Pietsch, Torsten; Figarella-Branger, Dominique

2017-09-01

The central nervous system (CNS) high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a recently described molecular entity. We report 3 new CNS HGNET-BCOR cases sharing common clinical presentation and pathologic features. The 3 cases concerned children aged 3 to 7 years who presented with a voluminous mass of the cerebellum. Pathologic features included proliferation of uniform spindle to ovoid cells with fine chromatin associated with a rich arborizing capillary network. Methylation profiling classified these cases as CNS HGNET-BCOR tumors. Polymerase chain reaction analysis confirmed the presence of internal tandem duplications in the C-terminus of BCOR (BCOR-ITD), a characteristic of these tumors, in all 3 cases. Immunohistochemistry showed a strong nuclear BCOR expression. In 2 cases, local recurrence occurred within 6 months. The third case, a patient who received a craniospinal irradiation after total surgical removal followed by a metronomics maintenance with irinotecan, temozolomide, and itraconazole, is still free of disease 14 months after diagnosis. In summary, CNS HGNET-BCOR represents a rare tumor occurring in young patients with dismal prognosis. BCOR nuclear immunoreactivity is highly suggestive of a BCOR-ITD. Whether CNS HGNET-BCOR should be classified among the category of "embryonal tumors" or within the category of "mesenchymal, nonmeningothelial tumors" remains to be clarified. Because CNS HGNET-BCOR share pathologic features and characteristic BCOR-ITD with clear cell sarcoma of the kidney, these tumors may represent local variants of the same entity.

Effects of nozzle-strut integrated design concepton on the subsonic turbine stage flowfield

NASA Astrophysics Data System (ADS)

Liu, Jun; Du, Qiang; Liu, Guang; Wang, Pei; Zhu, Junqiang

2014-10-01

In order to shorten aero-engine axial length, substituting the traditional long chord thick strut design accompanied with the traditional low pressure(LP) stage nozzle, LP turbine is integrated with intermediate turbine duct (ITD). In the current paper, five vanes of the first stage LP turbine nozzle is replaced with loaded struts for supporting the engine shaft, and providing oil pipes circumferentially which fulfilled the areo-engine structure requirement. However, their bulky geometric size represents a more effective obstacle to flow from high pressure (HP) turbine rotor. These five struts give obvious influence for not only the LP turbine nozzle but also the flowfield within the ITD, and hence cause higher loss. Numerical investigation has been undertaken to observe the influence of the Nozzle-Strut integrated design concept on the flowfield within the ITD and the nearby nozzle blades. According to the computational results, three main conclusions are finally obtained. Firstly, a noticeable low speed area is formed near the strut's leading edge, which is no doubt caused by the potential flow effects. Secondly, more severe radial migration of boundary layer flow adjacent to the strut's pressure side have been found near the nozzle's trailing edge. Such boundary layer migration is obvious, especially close to the shroud domain. Meanwhile, radial pressure gradient aggravates this phenomenon. Thirdly, velocity distribution along the strut's pressure side on nozzle's suction surface differs, which means loading variation of the nozzle. And it will no doubt cause nonuniform flowfield faced by the downstream rotor blade.

Aging effects on the binaural interaction component of the auditory brainstem response in the Mongolian gerbil: Effects of interaural time and level differences.

PubMed

Laumen, Geneviève; Tollin, Daniel J; Beutelmann, Rainer; Klump, Georg M

2016-07-01

The effect of interaural time difference (ITD) and interaural level difference (ILD) on wave 4 of the binaural and summed monaural auditory brainstem responses (ABRs) as well as on the DN1 component of the binaural interaction component (BIC) of the ABR in young and old Mongolian gerbils (Meriones unguiculatus) was investigated. Measurements were made at a fixed sound pressure level (SPL) and a fixed level above visually detected ABR threshold to compensate for individual hearing threshold differences. In both stimulation modes (fixed SPL and fixed level above visually detected ABR threshold) an effect of ITD on the latency and the amplitude of wave 4 as well as of the BIC was observed. With increasing absolute ITD values BIC latencies were increased and amplitudes were decreased. ILD had a much smaller effect on these measures. Old animals showed a reduced amplitude of the DN1 component. This difference was due to a smaller wave 4 in the summed monaural ABRs of old animals compared to young animals whereas wave 4 in the binaural-evoked ABR showed no age-related difference. In old animals the small amplitude of the DN1 component was correlated with small binaural-evoked wave 1 and wave 3 amplitudes. This suggests that the reduced peripheral input affects central binaural processing which is reflected in the BIC. Copyright © 2016 Elsevier B.V. All rights reserved.

Idaho Transportation Department : 2010 research program peer exchange.

DOT National Transportation Integrated Search

2010-05-01

The objectives of the peer exchange were to: : 1. Identify strengths, challenges, and opportunities for program and project management; : 2. Understand management expectations of the ITD Research Program; : 3. Review processes for project selection a...

Evaluating Performance of Highway Safety Projects

DOT National Transportation Integrated Search

2016-12-01

The purpose of this project was to investigate and document methods that the Idaho Transportation Department (ITD) and Local Highway Technical Assistance Council (LHTAC) can use to evaluate the performance of safety projects that have been implemente...

Growing a Constructive Culture at ITD

DOT National Transportation Integrated Search

2016-06-01

The Center for Health and Safety Culture evaluated the progress of the Idaho Transportation Departments effort to transform its culture. In 2012, a representative sample of employees identified a constructive culture as the ideal culture that woul...

Idaho Transportation Department 2009 partnership survey.

DOT National Transportation Integrated Search

2010-06-01

The report discusses the results of an electronic survey of 1,500 individual stakeholders of the Idaho Transportation Department (ITD). The purpose of this survey, which was conducted in August and September 2009, was to gauge stakeholders satisfa...

Influence of Reynolds Number on the Unsteady Aerodynamics of Integrated Aggressive Intermediate Turbine Duct

NASA Astrophysics Data System (ADS)

Liu, Hongrui; Liu, Jun; Ji, Lucheng; Du, Qiang; Liu, Guang; Wang, Pei

2018-06-01

The ultra-high bypass ratio turbofan engine attracts more and more attention in modern commercial engine due to advantages of high efficiency and low Specific Fuel Consumption (SFC). One of the characteristics of ultra-high bypass ratio turbofan is the intermediate turbine duct which guides the flow leaving high pressure turbine (HPT) to low pressure turbine (LPT) at a larger diameter, and this kind of design will lead to aggressive intermediate turbine duct (AITD) design concept. Thus, it is important to design the AITD without any severe loss. From the unsteady flow's point of view, in actual operating conditions, the incoming wake generated by HPT is unsteady which will take influence on boundary layer's transition within the ITD and LPT. In this paper, the three-dimensional unsteady aerodynamics of an AITD taken from a real engine is studied. The results of fully unsteady three-dimensional numerical simulations, performed with ANSYS-CFX (RANS simulation with transitional model), are critically evaluated against experimental data. After validation of the numerical model, the physical mechanisms inside the flow channel are analyzed, with an aim to quantify the sensitivities of different Reynolds number effect on both the ITD and LPT nozzle. Some general physical mechanisms can be recognized in the unsteady environment. It is recognized that wake characteristics plays a crucial role on the loss within both the ITD and LPT nozzle section, determining both time-averaged and time-resolved characteristics of the flow field. Meanwhile, particular attention needs to be paid to the unsteady effect on the boundary layer of LPT nozzle's suction side surface.

Bundled Postconditioning Therapies Improve Hemodynamics and Neurologic Recovery after 17 Minutes of Untreated Cardiac Arrest

PubMed Central

Bartos, Jason A.; Matsuura, Timothy R.; Sarraf, Mohammad; Youngquist, Scott T.; McKnite, Scott H.; Rees, Jennifer N.; Sloper, Daniel T.; Bates, Frank S.; Segal, Nicolas; Debaty, Guillaume; Lurie, Keith G.; Neumar, Robert W.; Metzger, Joseph M.; Riess, Matthias L.; Yannopoulos, Demetris

2014-01-01

Objective Ischemic postconditioning (stutter CPR) and sevoflurane have been shown to mitigate the effects of reperfusion injury in cardiac tissue after 15 minutes of ventricular fibrillation (VF) cardiac arrest. Poloxamer 188 (P188) has also proven beneficial to neuronal and cardiac tissue during reperfusion injury in human and animal models. We hypothesized that the use of stutter CPR, sevoflurane, and P188 combined with standard advanced life support would improve post-resuscitation cardiac and neurologic function after prolonged VF arrest. Methods Following 17 minutes of untreated VF, 20 pigs were randomized to Control treatment with active compression/decompression (ACD) CPR and impedance threshold device (ITD) (n=8) or Bundle therapy with stutter ACD CPR + ITD + sevoflurane + P188 (n=12). Epinephrine and post-resuscitation hypothermia were given in both groups per standard protocol. Animals that achieved return of spontaneous circulation (ROSC) were evaluated with echocardiography, biomarkers, and a blinded neurologic assessment with a cerebral performance category score. Results Bundle therapy improved hemodynamics during resuscitation, reduced need for epinephrine and repeated defibrillation, reduced biomarkers of cardiac injury and end-organ dysfunction, and increased left ventricular ejection fraction compared to Controls. Bundle therapy also improved rates of ROSC (100% vs. 50%), freedom from major adverse events (50% vs. 0% at 48 hours), and neurologic function (42% with mild or no neurologic deficit and 17% achieving normal function at 48 hours). Conclusions Bundle therapy with a combination of stutter ACD CPR, ITD, sevoflurane, and P188 improved cardiac and neurologic function after 17 minutes of untreated cardiac arrest in pigs. PMID:25447036

Potent Activity of Ponatinib (AP24534) in Models of FLT3-Driven Acute Myeloid Leukemia and Other Hematologic Malignancies

PubMed Central

Gozgit, Joseph M.; Wong, Matthew J.; Wardwell, Scott; Tyner, Jeffrey W.; Loriaux, Marc M.; Mohemmad, Qurish K.; Narasimhan, Narayana I.; Shakespeare, William C.; Wang, Frank; Druker, Brian J.; Clackson, Tim; Rivera, Victor M.

2011-01-01

Ponatinib (AP24534) is a novel multitargeted kinase inhibitor that potently inhibits native and mutant BCR-ABL at clinically achievable drug levels. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor α (PDGFRα). Here, using leukemic cell lines containing activated forms of each of these receptors, we show that ponatinib potently inhibits receptor phosphorylation and cellular proliferation with IC50 values comparable to those required for inhibition of BCR-ABL (0.3 to 20 nmol/L). The activity of ponatinib against the FLT3-ITD mutant, found in up to 30% of acute myeloid leukemia (AML) patients, was particularly notable. In MV4-11 (FLT3-ITD+/+) but not RS4;11 (FLT3-ITD−/−) AML cells, ponatinib inhibited FLT3 signaling and induced apoptosis at concentrations of less than 10 nmol/L. In an MV4-11 mouse xenograft model, once daily oral dosing of ponatinib led to a dose-dependent inhibition of signaling and tumor regression. Ponatinib inhibited viability of primary leukemic blasts from a FLT3-ITD positive AML patient (IC50 4 nmol/L) but not those isolated from 3 patients with AML expressing native FLT3. Overall, these results support the investigation of ponatinib in patients with FLT3-ITD–driven AML and other hematologic malignancies driven by KIT, FGFR1, or PDGFRα. PMID:21482694

Clinical characteristics of pigment dispersion syndrome in Chinese patients.

PubMed

Qing, G; Wang, N; Tang, X; Zhang, S; Chen, H

2009-08-01

To report clinical findings and characteristics of pigment dispersion syndrome (PDS) in Chinese patients. PDS suspects with any one of the following signs: corneal endothelial pigmentation, iris transillumination defects (ITDs), pigment granule dusting on anterior iris surface, posterior iris bowing, trabecular meshwork (TM) pigmentation, and lenticular or zonular pigmentation were evaluated for PDS at the glaucoma specialty clinic at Beijing Tongren Eye Centre. Diagnosis of PDS required at least two of the following signs: Krukenberg spindle, moderate-to-heavy TM pigmentation (>or=Scheie II) and any degree of lenticular and/or zonular pigmentation. Eighteen patients (12 males and six females) were identified as having PDS during a 1-year period, with mean age of 35.5+/-7.0 years (range, 22-49). All but two eyes from two patients had myopia of -0.5 D or greater, with mean spherical equivalent power of -5.20+/-5.80 D (range, -24.75+/-0.5). The average IOP at initial diagnosis was 33.7+/-10.5 mm Hg (range, 16-56). Fifteen patients (83.3%) were found to have pigmentary glaucoma at their initial diagnosis. All patients showed homogenous increased TM pigmentation as well as lenticular and/or zonular pigmentation. 61.1% of patients (11 of 18) had Krukenberg spindle. None of the patients exhibited spoke-like midperipheral ITDs except for trace-isolated transillumination in both eyes of the two patients. The most common clinical findings in Chinese PDS patients include homogeneous TM pigmentation and pigment granule dusting on lens zonules and/or posterior peripheral lens surface. ITDs are uncommon in Chinese patients with PDS.

An extremely high dietary iodide supply forestalls severe hypothyroidism in Na+/I- symporter (NIS) knockout mice.

PubMed

Ferrandino, Giuseppe; Kaspari, Rachel R; Reyna-Neyra, Andrea; Boutagy, Nabil E; Sinusas, Albert J; Carrasco, Nancy

2017-07-13

The sodium/iodide symporter (NIS) mediates active iodide (I - ) accumulation in the thyroid, the first step in thyroid hormone (TH) biosynthesis. Mutations in the SLC5A5 gene encoding NIS that result in a non-functional protein lead to congenital hypothyroidism due to I - transport defect (ITD). ITD is a rare autosomal disorder that, if not treated promptly in infancy, can cause mental retardation, as the TH decrease results in improper development of the nervous system. However, in some patients, hypothyroidism has been ameliorated by unusually large amounts of dietary I - . Here we report the first NIS knockout (KO) mouse model, obtained by targeting exons 6 and 7 of the Slc5a5 gene. In NIS KO mice, in the thyroid, stomach, and salivary gland, NIS is absent, and hence there is no active accumulation of the NIS substrate pertechnetate ( 99m TcO 4 - ). NIS KO mice showed undetectable serum T 4 and very low serum T 3 levels when fed a diet supplying the minimum I - requirement for rodents. These hypothyroid mice displayed oxidative stress in the thyroid, but not in the brown adipose tissue or liver. Feeding the mice a high-I - diet partially rescued TH biosynthesis, demonstrating that, at high I - concentrations, I - enters the thyroid through routes other than NIS.

Genetic instability in inherited and sporadic leukemias.

PubMed

Popp, Henning D; Bohlander, Stefan K

2010-12-01

Genetic instability due to increased DNA damage and altered DNA repair is of central significance in the initiation and progression of inherited and sporadic human leukemias. Although very rare, some inherited DNA repair insufficiency syndromes (e.g., Fanconi anemia, Bloom's syndrome) have added substantially to our understanding of crucial mechanisms of leukemogenesis in recent years. Conversely, sporadic leukemias account for the main proportion of leukemias and here DNA damaging reactive oxygen species (ROS) play a central role. Although the exact mechanisms of increased ROS production remain largely unknown and no single pathway has been detected thus far, some oncogenic proteins (e.g., the activated tyrosine kinases BCR-ABL1 and FLT3-ITD) seem to play a key role in driving genetic instability by increased ROS generation which influences the disease course (e.g., blast crisis in chronic myeloid leukemia or relapse in FLT3-ITD positive acute myeloid leukemia). Of course other mechanisms, which promote genetic instability in leukemia also exist. A newly emerging mechanism is the genome-wide alteration of epigenetic marks (e.g., hypomethylation of histone H3K79), which promotes chromosomal instability. Taken together genetic instability plays a critical role both in inherited and sporadic leukemias and emerges as a common theme in both inherited and sporadic leukemias. Beyond its theoretical impact, the analysis of genetic instability may lead the way to the development of innovative therapy strategies. © 2010 Wiley-Liss, Inc.

Implementation of the MEPDG for flexible pavements in Idaho.

DOT National Transportation Integrated Search

2012-05-01

This study was conducted to assist the Idaho Transportation Department (ITD) in the implementation of the Mechanistic-Empirical Pavement Design Guide (MEPDG) for flexible pavements. The main research work in this study focused on establishing a mater...

Midostaurin and Decitabine in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia and FLT3 Mutation

ClinicalTrials.gov

2017-11-29

Acute Myeloid Leukemia With FLT3/ITD Mutation; Acute Myeloid Leukemia With Gene Mutations; FLT3 Tyrosine Kinase Domain Point Mutation; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Idaho Transportation Department 2009 customer satisfaction survey.

DOT National Transportation Integrated Search

2010-02-01

In the summer and fall of 2009, the Idaho Transportation Department (ITD) commissioned a statewide customer satisfaction survey of Idaho residents in order to assess the overall level of satisfaction with several key areas of service provided by the ...

Acoustic Database for Turbofan Engine Core-Noise Sources. I; Volume

NASA Technical Reports Server (NTRS)

Gordon, Grant

2015-01-01

In this program, a database of dynamic temperature and dynamic pressure measurements were acquired inside the core of a TECH977 turbofan engine to support investigations of indirect combustion noise. Dynamic temperature and pressure measurements were recorded for engine gas dynamics up to temperatures of 3100 degrees Fahrenheit and transient responses as high as 1000 hertz. These measurements were made at the entrance of the high pressure turbine (HPT) and at the entrance and exit of the low pressure turbine (LPT). Measurements were made at two circumferential clocking positions. In the combustor and inter-turbine duct (ITD), measurements were made at two axial locations to enable the exploration of time delays. The dynamic temperature measurements were made using dual thin-wire thermocouple probes. The dynamic pressure measurements were made using semi-infinite probes. Prior to the engine test, a series of bench, oven, and combustor rig tests were conducted to characterize the performance of the dual wire temperature probes and to define and characterize the data acquisition systems. A measurement solution for acquiring dynamic temperature and pressure data on the engine was defined. A suite of hardware modifications were designed to incorporate the dynamic temperature and pressure instrumentation into the TECH977 engine. In particular, a probe actuation system was developed to protect the delicate temperature probes during engine startup and transients in order to maximize sensor life. A set of temperature probes was procured and the TECH977 engine was assembled with the suite of new and modified hardware. The engine was tested at four steady state operating speeds, with repeats. Dynamic pressure and temperature data were acquired at each condition for at least one minute. At the two highest power settings, temperature data could not be obtained at the forward probe locations since the mean temperatures exceeded the capability of the probes. The temperature data were processed using software that accounts for the effects of convective and conductive heat transfer. The software was developed under previous NASA sponsored programs. Compensated temperature spectra and compensated time histories corresponding to the dynamic temperature of the gas stream were generated. Auto-spectral and cross-spectral analyses of the data were performed to investigate spectral features, acoustic circumferential mode content, signal coherence, and time delays. The dynamic temperature data exhibit a wideband and fairly flat spectral content. The temperature spectra do not change substantially with operating speed. The pressure spectra in the combustor and ITD exhibit generally similar shapes and amplitudes, making it difficult to identify any features that suggest the presence of indirect combustion noise. Cross-spectral analysis reveal a strong correlation between pressure and temperature fluctuations in the ITD, but little correlation between temperature fluctuations at the entrance of the HPT and pressure fluctuations downstream of it. Temperature fluctuations at the entrance of the low pressure turbine were an order of magnitude smaller than those at the entrance to the high pressure turbine. Time delay analysis of the temperature fluctuations in the combustor was inconclusive, perhaps due to the substantial mixing that occurs between the upstream and downstream locations. Time delay analysis of the temperature fluctuations in the ITD indicate that they convect at the mean flow speed. Analysis of the data did not reveal any convincing indications of the presence of indirect combustion noise. However, this analysis has been preliminary and additional exploration of the data is recommended including the use of more sophisticated signal processing to explore subtle issues that have been revealed but which are not yet fully understood or explained.

Evaluation of Fiber-Reinforced Asphalt Pavements : Laboratory Study

DOT National Transportation Integrated Search

2016-06-01

The Idaho Transportation Department (ITD) initiated a field project to evaluate the effectiveness of using fibers to mitigate rutting and fatigue distresses at US-30 east of Montpelier in south Idaho. The project was constructed in August 2014 to add...

Highway user expectations for ITD winter maintenance.

DOT National Transportation Integrated Search

2014-07-01

Providing a high Level of Service (LOS) to ensure the safety and mobility for the traveling public is a key objective for winter : maintenance operations. The goal of this research was to obtain a better understanding of Idaho highway users expect...

Methodology for prioritizing appropriate mitigation actions to reduce wildlife-vehicle collisions on Idaho highways.

DOT National Transportation Integrated Search

2014-08-01

Vehicle collisions with large wild animals are a safety issue for motorists and an ecological concern for : wildlife populations. The objective of this research was to advance the efficacy of Idaho Transportation : Departments (ITDs) project pl...

77 FR 15181 - Notice To Rescind the Notice of Intent To Prepare an Environmental Impact Statement, Valley...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-14

... cooperation with Idaho Transportation Department (ITD) published a Notice of Intent (NOI) on January 24, 2000... Valley, on SH-55. A series of project team meetings/ public workshops were held and a range of...

Methodology for prioritizing appropriate mitigation actions to reduce wildlife-vehicle collisions on Idaho highways.

DOT National Transportation Integrated Search

2014-08-01

Vehicle collisions with large wild animals are a safety issue for motorists and an ecological concern for wildlife populations. The objective of this research was to advance the efficacy of Idaho Transportation Departments (ITDs) project planni...

Impacts of using salt and salt brine for roadway deicing.

DOT National Transportation Integrated Search

2014-06-01

Idaho Transportation Department (ITD) uses a variety of methods to help ensure safe travel on the state highway system : following winter storm events. These methods include plowing, use of sand to improve traction, and use of salt and chemical : com...

Lithologic characterization of active ITD aggregate sources and implications for aggregate quality.

DOT National Transportation Integrated Search

2014-03-01

Aggregate from 40 material sources across Idaho were sampled and the lithologies identified quantitatively. Aggregate compositions are compared with commercial AASHTO T 303 and ASTM C1293 results and the geologic map of Idaho to identify those rock t...

Material acceptance risk analysis : superpave hot mix asphalt.

DOT National Transportation Integrated Search

2010-09-01

The objective of this study is to review Superpave Hot Mix asphalt used by other state DOTs and make recommendation to Idaho Transportation Department (ITD) in using this product in its roadways and in particular in low-traffic roadways. Based on the...

Evaluation of the Boussignac Cardiac arrest device (B-card) during cardiopulmonary resuscitation in an animal model.

PubMed

Moore, Johanna C; Lamhaut, Lionel; Hutin, Alice; Dodd, Kenneth W; Robinson, Aaron E; Lick, Michael C; Salverda, Bayert J; Hinke, Mason B; Labarere, José; Debaty, Guillaume; Segal, Nicolas

2017-10-01

The purpose of this study was to examine continuous oxygen insufflation (COI) in a swine model of cardiac arrest. The primary hypothesis was COI during standard CPR (S-CPR) should result in higher intrathoracic pressure (ITP) during chest compression and lower ITP during decompression versus S-CPR alone. These changes with COI were hypothesized to improve hemodynamics. The second hypothesis was that changes in ITP with S-CPR+COI would result in superior hemodynamics compared with active compression decompression (ACD) + impedance threshold device (ITD) CPR, as this method primarily lowers ITP during chest decompression. After 6min of untreated ventricular fibrillation, S-CPR was initiated in 8 female swine for 4min, then 3min of S-CPR+COI, then 3min of ACD+ITD CPR, then 3min of S-CPR+COI. ITP and hemodynamics were continuously monitored. During S-CPR+COI, ITP was always positive during the CPR compression and decompression phases. ITP compression values with S-CPR+COI versus S-CPR alone were 5.5±3 versus 0.2±2 (p<0.001) and decompression values were 2.8±2 versus -1.3±2 (p<0.001), respectively. With S-CPR+COI versus ACD+ITD the ITP compression values were 5.5±3 versus 1.5±2 (p<0.01) and decompression values were 2.8±2 versus -4.7±3 (p<0.001), respectively. COI during S-CPR created a continuous positive pressure in the airway during both the compression and decompression phase of CPR. At no point in time did COI generate a negative intrathoracic pressures during CPR in this swine model of cardiac arrest. Copyright © 2017 Elsevier B.V. All rights reserved.

Allogeneic stem cell transplantation benefits for patients ≥ 60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

PubMed Central

Poiré, Xavier; Labopin, Myriam; Polge, Emmanuelle; Passweg, Jakob; Craddock, Charles; Blaise, Didier; Cornelissen, Jan J.; Volin, Liisa; Russell, Nigel H.; Socié, Gérard; Michallet, Mauricette; Fegueux, Nathalie; Chevallier, Patrice; Brecht, Arne; Hunault-Berger, Mathilde; Mohty, Mohamad; Esteve, Jordi; Nagler, Arnon

2018-01-01

Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3-ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively (P<0.005). Non-relapse mortality for the entire cohort was 20%. In multivariate analysis, disease status at transplantation was the most powerful predictor of worse leukemia-free survival, graft-versus-host disease and relapse-free survival, and overall survival. In this elderly population, age was not associated with outcome. Based on the current results, allogeneic transplantation translates into a favorable outcome in fit patients ≥ 60 with FLT3-ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients. PMID:29242299

Clinical Outcome of Inter-Proximal Papilla between a Tooth and a Single Implant Treated with CAD/CAM Abutments: a Cross-Sectional Study

PubMed Central

Lima, Tiago; Carvalho, Ágata; Carvalho, Vasco

2012-01-01

ABSTRACT Objectives The aim of this study was to assess the clinical outcomes achieved with Computer-Assisted Design/Computer-Assisted Manufacturing implant abutments in the anterior maxilla. Material and Methods Nineteen patients with a mean age of 41 (range form 26 to 63) years, treated with 21 single tooth implants and 21 Computer-Assisted Design/Computer-Assisted Manufacturing (CAD/CAM) abutments in the anterior maxillary region were included in this study. The patients followed 4 criteria of inclusion: (1) had a single-tooth implant in the anterior maxilla, (2) had a CAD/CAM abutment, (3) had a contralateral natural tooth, (4) the implant was restored and in function for at least 6 months up to 2 years. Cases without contact point were excluded. Presence/absence of the interproximal papilla, inter tooth-implant distance (ITD) and distance from the base of the contact point to dental crest bone of adjacent tooth (CPB) were accessed. Results Forty interproximal spaces were evaluated, with an average mesial CPB of 5.65 (SD 1.65) mm and distal CPB of 4.65 (SD 1.98) mm. An average mesial ITD of 2.49 (SD 0.69) mm and an average distal ITD of 1.89 (SD 0.63) mm were achieved. Papilla was present in all the interproximal spaces accessed. Conclusions The restoration of dental implants using CAD/CAM abutments is a predictable treatment with improved aesthetic results. These type of abutments seem to help maintaining a regular papillary filling although the variations of the implant positioning or the restoration teeth relation. PMID:24422016

Does the relief of glucose toxicity act as a mediator in proliferative actions of vanadium on pancreatic islet beta cells in streptozocin diabetic rats?

PubMed

Pirmoradi, Leila; Mohammadi, Mohammad Taghi; Safaei, Akbar; Mesbah, Fakhardin; Dehghani, Gholam Abbas

2014-07-01

Data shows vanadium protects pancreatic beta cells (BC) from diabetic animals. Whether this effect is direct or through the relief of glucose toxicity is not clear. This study evaluated the potential effect of oral vanadyl sulfate (vanadium) on glycemic status and pancreatic BC of normal and diabetic rats. Rats were divided into five groups of normal and diabetic. Diabetes was induced with streptozocin (40 mg/kg, i.v.). Normal rats used water (CN) or vanadium (1 mg/ml VOSO4, VTN). Diabetic rats used water (CD), water plus daily neutral protamine Hagedorn insulin injection (80 U/kg, ITD) or vanadium (VTD). Blood samples were taken for blood glucose (BG, mg/dL) and insulin (ng/dL) measurements. After two months, the pancreata of sacrificed rats were prepared for islet staining. Pre-treated normal BG was 88 ± 2, and diabetic BG was 395 ± 9. The final BG in CD, VTD, and ITD was 509 ± 22, 138 ± 14, and 141 ± 14, respectively. Insulin in VTN (0.75 ± 0.01) and VTD (0.78 ± 0.01) was similar, higher than CD (0.51 ± 0.07) but lower than CN (2.51 ± 0.02). VTN islets compared to CN had larger size and denser central core insulin immunoreactivity with plentiful BC. CD and ITD islets were atrophied and had scattered insulin immunoreactivity spots and low BC mass. VTD islets were almost similar to CN. Besides insulin-like activity, vanadium protected pancreatic islet BC, and the relief of glucose toxicity happening with vanadium had a little role in this action.

Does the Relief of Glucose Toxicity Act As a Mediator in Proliferative Actions of Vanadium on Pancreatic Islet Beta Cells in Streptozocin Diabetic Rats?

PubMed Central

Pirmoradi, Leila; Mohammadi, Mohammad Taghi; Safaei, Akbar; Mesbah, Fakhardin; Dehghani, Gholam Abbas

2014-01-01

Background: Data shows vanadium protects pancreatic beta cells (BC) from diabetic animals. Whether this effect is direct or through the relief of glucose toxicity is not clear. This study evaluated the potential effect of oral vanadyl sulfate (vanadium) on glycemic status and pancreatic BC of normal and diabetic rats. Methods: Rats were divided into five groups of normal and diabetic. Diabetes was induced with streptozocin (40 mg/kg, i.v.). Normal rats used water (CN) or vanadium (1 mg/ml VOSO4, VTN). Diabetic rats used water (CD), water plus daily neutral protamine Hagedorn insulin injection (80 U/kg, ITD) or vanadium (VTD). Blood samples were taken for blood glucose (BG, mg/dL) and insulin (ng/dL) measurements. After two months, the pancreata of sacrificed rats were prepared for islet staining. Results: Pre-treated normal BG was 88 ± 2, and diabetic BG was 395 ± 9. The final BG in CD, VTD, and ITD was 509 ± 22, 138 ± 14, and 141 ± 14, respectively. Insulin in VTN (0.75 ± 0.01) and VTD (0.78 ± 0.01) was similar, higher than CD (0.51 ± 0.07) but lower than CN (2.51 ± 0.02). VTN islets compared to CN had larger size and denser central core insulin immunoreactivity with plentiful BC. CD and ITD islets were atrophied and had scattered insulin immunoreactivity spots and low BC mass. VTD islets were almost similar to CN. Conclusion: Besides insulin-like activity, vanadium protected pancreatic islet BC, and the relief of glucose toxicity happening with vanadium had a little role in this action. PMID:24842144

Pelvimetry in nulliparous and primiparous women using 3 Tesla magnetic resonance imaging.

PubMed

Hampel, Franziska; Hallscheidt, Peter; Sohn, Christof; Schlehe, Bettina; Brocker, Kerstin A

2018-02-21

To perform pelvimetry in nulliparous and primiparous women using 3 Tesla magnetic resonance imaging (3T MRI). Twenty-five nulliparous volunteers and 25 primiparous women underwent pelvic 3T MRI within one week after vaginal childbirth in a prospective clinical single-center trial. The pelvimetric parameters interspinous distance (ISD), intertuberous distance (ITD), sagittal outlet (SO), obstetric conjugate (OC), and coccygeal curved length (CCL) were adapted from anthropometric measurements as well as from sonographic and computed tomography-based pelvimetry performed on high-resolution T2-weighted images. We compared the results of the two study groups to one another, recent literature and postpartum-diagnosed levator ani muscle (LAM) injuries. The mean values for primipara/nullipara were ISD 107 ± 8.3/105 ± 8.4 mm, ITD 119.8 ± 10.2/118.4 ± 13.1 mm, OC 129.4 ± 10/130.8 ± 6.9 mm, SO 114.3 ± 7.8/112.5 ± 8.9 mm, and CCL 37.3 ± 7.4/39 ± 8 mm. Significant differences (P < 0.05) were found between the results for OC, SO, and CCL (primipara) and ISD, ITD and OC (nullipara) and the values in the literature. No significant difference in pelvimetric values was found between the groups. A significant correlation was found between the pelvimetric parameters and five types of LAM injuries. Two-dimensional 3T MRI combines high-resolution images with objective pelvimetric measurements applicable in a postpartum setting. Our results provide a good foundation for further MRI-based studies evaluating the bony pelvis and its relation to LAM injuries during vaginal childbirth. © 2018 Wiley Periodicals, Inc.

Relative size of auditory pathways in symmetrically and asymmetrically eared owls.

PubMed

Gutiérrez-Ibáñez, Cristián; Iwaniuk, Andrew N; Wylie, Douglas R

2011-01-01

Owls are highly efficient predators with a specialized auditory system designed to aid in the localization of prey. One of the most unique anatomical features of the owl auditory system is the evolution of vertically asymmetrical ears in some species, which improves their ability to localize the elevational component of a sound stimulus. In the asymmetrically eared barn owl, interaural time differences (ITD) are used to localize sounds in azimuth, whereas interaural level differences (ILD) are used to localize sounds in elevation. These two features are processed independently in two separate neural pathways that converge in the external nucleus of the inferior colliculus to form an auditory map of space. Here, we present a comparison of the relative volume of 11 auditory nuclei in both the ITD and the ILD pathways of 8 species of symmetrically and asymmetrically eared owls in order to investigate evolutionary changes in the auditory pathways in relation to ear asymmetry. Overall, our results indicate that asymmetrically eared owls have much larger auditory nuclei than owls with symmetrical ears. In asymmetrically eared owls we found that both the ITD and ILD pathways are equally enlarged, and other auditory nuclei, not directly involved in binaural comparisons, are also enlarged. We suggest that the hypertrophy of auditory nuclei in asymmetrically eared owls likely reflects both an improved ability to precisely locate sounds in space and an expansion of the hearing range. Additionally, our results suggest that the hypertrophy of nuclei that compute space may have preceded that of the expansion of the hearing range and evolutionary changes in the size of the auditory system occurred independently of phylogeny. Copyright © 2011 S. Karger AG, Basel.

The influence of imagery vividness on cognitive and perceptual cues in circular auditorily-induced vection.

PubMed

Väljamäe, Aleksander; Sell, Sara

2014-01-01

In the absence of other congruent multisensory motion cues, sound contribution to illusions of self-motion (vection) is relatively weak and often attributed to purely cognitive, top-down processes. The present study addressed the influence of cognitive and perceptual factors in the experience of circular, yaw auditorily-induced vection (AIV), focusing on participants imagery vividness scores. We used different rotating sound sources (acoustic landmark vs. movable types) and their filtered versions that provided different binaural cues (interaural time or level differences, ITD vs. ILD) when delivering via loudspeaker array. The significant differences in circular vection intensity showed that (1) AIV was stronger for rotating sound fields containing auditory landmarks as compared to movable sound objects; (2) ITD based acoustic cues were more instrumental than ILD based ones for horizontal AIV; and (3) individual differences in imagery vividness significantly influenced the effects of contextual and perceptual cues. While participants with high scores of kinesthetic and visual imagery were helped by vection "rich" cues, i.e., acoustic landmarks and ITD cues, the participants from the low-vivid imagery group did not benefit from these cues automatically. Only when specifically asked to use their imagination intentionally did these external cues start influencing vection sensation in a similar way to high-vivid imagers. These findings are in line with the recent fMRI work which suggested that high-vivid imagers employ automatic, almost unconscious mechanisms in imagery generation, while low-vivid imagers rely on more schematic and conscious framework. Consequently, our results provide an additional insight into the interaction between perceptual and contextual cues when experiencing purely auditorily or multisensory induced vection.

The influence of imagery vividness on cognitive and perceptual cues in circular auditorily-induced vection

PubMed Central

Väljamäe, Aleksander; Sell, Sara

2014-01-01

In the absence of other congruent multisensory motion cues, sound contribution to illusions of self-motion (vection) is relatively weak and often attributed to purely cognitive, top-down processes. The present study addressed the influence of cognitive and perceptual factors in the experience of circular, yaw auditorily-induced vection (AIV), focusing on participants imagery vividness scores. We used different rotating sound sources (acoustic landmark vs. movable types) and their filtered versions that provided different binaural cues (interaural time or level differences, ITD vs. ILD) when delivering via loudspeaker array. The significant differences in circular vection intensity showed that (1) AIV was stronger for rotating sound fields containing auditory landmarks as compared to movable sound objects; (2) ITD based acoustic cues were more instrumental than ILD based ones for horizontal AIV; and (3) individual differences in imagery vividness significantly influenced the effects of contextual and perceptual cues. While participants with high scores of kinesthetic and visual imagery were helped by vection “rich” cues, i.e., acoustic landmarks and ITD cues, the participants from the low-vivid imagery group did not benefit from these cues automatically. Only when specifically asked to use their imagination intentionally did these external cues start influencing vection sensation in a similar way to high-vivid imagers. These findings are in line with the recent fMRI work which suggested that high-vivid imagers employ automatic, almost unconscious mechanisms in imagery generation, while low-vivid imagers rely on more schematic and conscious framework. Consequently, our results provide an additional insight into the interaction between perceptual and contextual cues when experiencing purely auditorily or multisensory induced vection. PMID:25520683

Weed-Suppressive Soil Bacteria to Reduce Cheatgrass and Improve Vegetation Diversity on ITD Rights-of-Way

DOT National Transportation Integrated Search

2017-06-01

Transportation departments are challenged by the invasion of downy brome (cheatgrass) and medusahead. The reduction of downy brome (cheat grass) by Weed Suppressive Bacteria (WSB) Pseudomonas fluorescens strain ACK55 was evaluated on roadsides of I-8...

Review of non-nuclear density gauges as possible replacements for ITD's nuclear density gauges.

DOT National Transportation Integrated Search

2015-01-01

This report examines the possibility of replacing nuclear density gauges (NDGs) with non-nuclear density gauges (NNDGs) to : measure density of hot mix asphalt (HMA) and unbound pavement layers in the field. The research team evaluated the : effectiv...

Seasonal evolution of the Arctic marginal ice zone and its power-law obeying floe size distribution

NASA Astrophysics Data System (ADS)

Zhang, J.; Stern, H. L., III; Schweiger, A. J. B.; Steele, M.; Hwang, P. B.

2017-12-01

A thickness, floe size, and enthalpy distribution (TFED) sea ice model, implemented numerically into the Pan-arctic Ice-Ocean Modeling and Assimilation System (PIOMAS), is used to investigate the seasonal evolution of the Arctic marginal ice zone (MIZ) and its floe size distribution. The TFED sea ice model, by coupling the Zhang et al. [2015] sea ice floe size distribution (FSD) theory with the Thorndike et al. [1975] ice thickness distribution (ITD) theory, simulates 12-category FSD and ITD explicitly and jointly. A range of ice thickness and floe size observations were used for model calibration and validation. The model creates FSDs that generally obey a power law or upper truncated power law, as observed by satellites and aerial surveys. In this study, we will examine the role of ice fragmentation and lateral melting in altering FSDs in the Arctic MIZ. We will also investigate how changes in FSD impact the seasonal evolution of the MIZ by modifying the thermodynamic processes.

Spatial cue reliability drives frequency tuning in the barn Owl's midbrain

PubMed Central

Cazettes, Fanny; Fischer, Brian J; Pena, Jose L

2014-01-01

The robust representation of the environment from unreliable sensory cues is vital for the efficient function of the brain. However, how the neural processing captures the most reliable cues is unknown. The interaural time difference (ITD) is the primary cue to localize sound in horizontal space. ITD is encoded in the firing rate of neurons that detect interaural phase difference (IPD). Due to the filtering effect of the head, IPD for a given location varies depending on the environmental context. We found that, in barn owls, at each location there is a frequency range where the head filtering yields the most reliable IPDs across contexts. Remarkably, the frequency tuning of space-specific neurons in the owl's midbrain varies with their preferred sound location, matching the range that carries the most reliable IPD. Thus, frequency tuning in the owl's space-specific neurons reflects a higher-order feature of the code that captures cue reliability. DOI: http://dx.doi.org/10.7554/eLife.04854.001 PMID:25531067

The relation between working memory capacity and auditory lateralization in children with auditory processing disorders.

PubMed

Moossavi, Abdollah; Mehrkian, Saiedeh; Lotfi, Yones; Faghihzadeh, Soghrat; sajedi, Hamed

2014-11-01

Auditory processing disorder (APD) describes a complex and heterogeneous disorder characterized by poor speech perception, especially in noisy environments. APD may be responsible for a range of sensory processing deficits associated with learning difficulties. There is no general consensus about the nature of APD and how the disorder should be assessed or managed. This study assessed the effect of cognition abilities (working memory capacity) on sound lateralization in children with auditory processing disorders, in order to determine how "auditory cognition" interacts with APD. The participants in this cross-sectional comparative study were 20 typically developing and 17 children with a diagnosed auditory processing disorder (9-11 years old). Sound lateralization abilities investigated using inter-aural time (ITD) differences and inter-aural intensity (IID) differences with two stimuli (high pass and low pass noise) in nine perceived positions. Working memory capacity was evaluated using the non-word repetition, and forward and backward digits span tasks. Linear regression was employed to measure the degree of association between working memory capacity and localization tests between the two groups. Children in the APD group had consistently lower scores than typically developing subjects in lateralization and working memory capacity measures. The results showed working memory capacity had significantly negative correlation with ITD errors especially with high pass noise stimulus but not with IID errors in APD children. The study highlights the impact of working memory capacity on auditory lateralization. The finding of this research indicates that the extent to which working memory influences auditory processing depend on the type of auditory processing and the nature of stimulus/listening situation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

ACHP | Working Together to Build a More Inclusive Preservation Program

Science.gov Websites

either work in a museum or teach. I was home for the summer and thought it'd be a good opportunity to even thought about the East Kong Yick Building as its possible new home, it was powerful to know that

76 FR 50268 - Amended Certification Regarding Eligibility To Apply for Worker Adjustment Assistance

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-12

... Certification Regarding Eligibility To Apply for Worker Adjustment Assistance TA-W-73,218 International Business... International Business Machines Corporation (IBM), ITD Business Unit, Division 7, Email and Collaboration Group..., the Department is amending this certification to include workers of International Business Machines...

Alternative Fuels Data Center

Science.gov Websites

Transportation Department (ITD) established the Connected and Autonomous Vehicle (CAV) Testing and Deployment testing and deployment of CAVs, coordinate with the identified agencies about how to administer the testing of CAVs on roads, review existing state statues and administrative rules that impede the testing

Road map for implementing the AASHTO pavement ME design software for the Idaho Transportation Department.

DOT National Transportation Integrated Search

2014-04-01

This report provides a Road Map for implementing the AASHTOWare Pavement ME Design software for the Idaho Transportation Department (ITD). The Road Map calls for a series of three stages: Stage 1 - Immediate, Stage 2 - Near Term, and Stage 3 - Future...

Flight Services and Aircraft Access: Active Flow Control Vertical Tail and Insect Accretion and Mitigation Flight Test

NASA Technical Reports Server (NTRS)

Whalen, Edward A.

2016-01-01

This document serves as the final report for the Flight Services and Aircraft Access task order NNL14AA57T as part of NASA Environmentally Responsible Aviation (ERA) Project ITD12A+. It includes descriptions of flight test preparations and execution for the Active Flow Control (AFC) Vertical Tail and Insect Accretion and Mitigation (IAM) experiments conducted on the 757 ecoDemonstrator. For the AFC Vertical Tail, this is the culmination of efforts under two task orders. The task order was managed by Boeing Research & Technology and executed by an enterprise-wide Boeing team that included Boeing Research & Technology, Boeing Commercial Airplanes, Boeing Defense and Space and Boeing Test and Evaluation. Boeing BR&T in St. Louis was responsible for overall Boeing project management and coordination with NASA. The 757 flight test asset was provided and managed by the BCA ecoDemonstrator Program, in partnership with Stifel Aircraft Leasing and the TUI Group. With this report, all of the required deliverables related to management of this task order have been met and delivered to NASA as summarized in Table 1. In addition, this task order is part of a broader collaboration between NASA and Boeing.

Changes in Arctic Sea Ice Thickness and Floe Size

NASA Astrophysics Data System (ADS)

Zhang, J.; Schweiger, A. J. B.; Stern, H. L., III; Steele, M.

2016-12-01

A thickness, floe size, and enthalpy distribution sea ice model was implemented into the Pan-arctic Ice-Ocean Modeling and Assimilation System (PIOMAS) by coupling the Zhang et al. [2015] sea ice floe size distribution (FSD) theory with the Thorndike et al. [1975] ice thickness distribution (ITD) theory in order to explicitly simulate multicategory FSD and ITD simultaneously. A range of ice thickness and floe size observations were used for model calibration and validation. The expanded, validated PIOMAS was used to study sea ice response to atmospheric and oceanic changes in the Arctic, focusing on the interannual variability and trends of ice thickness and floe size over the period 1979-2015. It is found that over the study period both ice thickness and floe size have been decreasing steadily in the Arctic. The simulated ice thickness shows considerable spatiotemporal variability in recent years. As the ice cover becomes thinner and weaker, the model simulates an increasing number of small floes (at the low end of the FSD), which affects sea ice properties, particularly in the marginal ice zone.

Predictive significance of the European LeukemiaNet classification of genetic aberrations in patients with acute myeloid leukaemia undergoing allogeneic stem cell transplantation.

PubMed

Hemmati, Philipp G; Vuong, Lam G; Terwey, Theis H; Jehn, Christian F; le Coutre, Philipp; Penack, Olaf; Na, Il-Kang; Dörken, Bernd; Arnold, Renate

2017-02-01

The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (alloSCT). We retrospectively analysed 274 patients transplanted at our centre between 2004 and 2014. The ELN grouping is comparable to the Southwest Oncology Group/Eastern Cooperative Oncology Group (SWOG/ECOG) stratification in predicting the outcome after alloSCT [overall P = 0.0064 for disease-free survival (DFS), overall P = 0.003 for relapse]. Patients with an intermediate-1 profile have a significantly elevated 5-yr relapse incidence as compared to favourable risk patients, that is 40% vs. 15%, [hazard ratio (HR) 2.58, P = 0.048]. An intermediate-1 risk profile is an independent predictor for relapse as determined by multivariate Cox regression analysis (HR 3.05, P = 0.023). In intermediate-1 patients, the presence of an FLT3 internal tandem duplication (FLT3-ITD) is associated with a significantly increased relapse incidence (P = 0.0323), and a lower DFS (P = 0.0465). FLT3-ITD is an independent predictor for overall survival, DFS and relapse incidence in the intermediate-1 subgroup. The ELN stratification of genetic risk predicts the outcome of patients with AML undergoing alloSCT. Patients with an intermediate-1 profile have a high risk for treatment failure due to relapse, which prompts the development of alternative treatment strategies. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Acute myeloid leukemia: 2013 update on risk-stratification and management.

PubMed

Estey, Elihu H

2013-04-01

Acute myeloid leukemia (AML) results from accumulation of abnormal blasts in the marrow. These cells interfere with normal hematopoiesis, can escape into the peripheral blood, and infiltrate CSF and lung. It is likely that many different mutations, epigenetic aberrations, or abnormalities in micro RNA expression can produce the same morphologic disease with these differences responsible for the very variable response to therapy, which is AMLs principal feature. This rests on demonstration that the marrow or blood has > 20% blasts of myeloid lineage. Blast lineage is assessed by multiparameter flow cytometry, with CD33 and CD13 being surface markers typically expressed by myeloid blasts. It should be realized that clinical/prognostic considerations, not the blast % per se, should be the main factor determining how a patient is treated. Two features determine risk: the probability of treatment-related mortality (TRM) and, more important, even in patients aged >75 with Zubrod performance status 1, the probability of resistance to standard therapy despite not incurring TRM. The chief predictor of resistance is cytogenetics, with a monosomal karyotype (MK) denoting the disease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant (HCT). The most common cytogentic finding is a normal karyotype(NK) and those of such patients with an NPM1 mutation but no FLT3 internal tandem duplication (ITD), or with a CEBPA mutation, have a prognosis similar to that of patients with the most favorable cytogenetics (inv 16 or t[8;21]) (60-70% cure rate). In contrast, NK patients with a FLT3 ITD have only a 30-40% chance of cure even after HCT. Accordingly analyses of NPM1, FLT3, and CEBPA should be part of routine evaluation, much as is cytogenetics. Risk is best assessed considering several variables simultaneously rather than, for example, only age. Increasing evidence indicates that other mutations and abnormalities in microRNA (miRNA) expression also affect resistance as do post treatment factors, in particular the presence of minimal residual disease. These newer mutations and MRD are discussed in this update. Patients with inv (16) or t(8;21) or who are NPM1+/FLT3ITD-can receive standard therapy (daunorubicin + cytarabine) and should not receive HCT in first CR. It seems likely that use of a daily daunorubicin dose of 90 mg/m(2) will further improve outcome in these patients. There appears no reason to use doses of cytarabine > 1 g/m(2) (for example bid X 6 days), as opposed to the more commonly used 3 g/m(2) . Patients with an unfavorable karyotype (particularly MK) are unlikely to benefit from standard therapy (even with dose escalation) and are thus prime candidates for clinical trials of new drugs or new approaches to HCT; the latter should be done in first CR. Patients with intermediate prognoses (for example NK and NPM and FLT3ITD negative) should also receive HCT in first CR and can plausibly receive either investigational or standard induction therapy, with the same prognostic information about standard therapy leading one patient to choose the standard and another an investigational option. This update discusses results with newer agents: quizartinib and crenolanib, gemtuzumab ozogamicin, clofarabine and cladribine, azacitidine and decitabine, volasertib, and means to prevent relapse after allogeneic transplant. The diagnosis of AML essentially is made as it was in 2012. Thus this review will emphasize new developments in risk stratification and treatment using as references many papers published in 2012. Copyright © 2013 Wiley Periodicals, Inc.

Allogeneic stem cell transplantation benefits for patients ≥ 60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

PubMed

Poiré, Xavier; Labopin, Myriam; Polge, Emmanuelle; Passweg, Jakob; Craddock, Charles; Blaise, Didier; Cornelissen, Jan J; Volin, Liisa; Russell, Nigel H; Socié, Gérard; Michallet, Mauricette; Fegueux, Nathalie; Chevallier, Patrice; Brecht, Arne; Hunault-Berger, Mathilde; Mohty, Mohamad; Esteve, Jordi; Nagler, Arnon

2018-02-01

Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 ( FLT3 -ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3 -ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively ( P <0.005). Non-relapse mortality for the entire cohort was 20%. In multivariate analysis, disease status at transplantation was the most powerful predictor of worse leukemia-free survival, graft- versus -host disease and relapse-free survival, and overall survival. In this elderly population, age was not associated with outcome. Based on the current results, allogeneic transplantation translates into a favorable outcome in fit patients ≥ 60 with FLT3 -ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients. Copyright© 2018 Ferrata Storti Foundation.

Impact of pre-transplantation minimal residual disease determined by multiparameter flow cytometry on the outcome of AML patients with FLT3-ITD after allogeneic stem cell transplantation.

PubMed

Zhao, Xiaosu; Wang, Zhidong; Ruan, Guorui; Liu, Yanrong; Wang, Yu; Zhang, Xiaohui; Xu, Lanping; Huang, Xiaojun; Chang, Yingjun

2018-06-01

In this study, using multiparameter flow cytometry (FCM), we investigate the impact of minimal residual disease prior to transplantation (pre-MRD) on the transplant outcomes of AML patients with fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutation. A total of 20 patients who received HLA-matched sibling donor transplantation (MSDT) and 63 patients who received unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) were enrolled. Patients were classified into four groups based on the status of pre-FCM: group 1 with positive pre-FCM before MSDT, group 2 with negative pre-FCM before MSDT, group 3 with positive pre-FCM before haplo-HSCT, and group 4 with positive pre-FCM before haplo-HSCT. The results showed that patients in group 1 had the highest cumulative incidence of relapse (2-year CIR, 75.0%), the lowest leukemia-free survival (2-year LFS, 33.3%), and the overall survival (2-year OS, 25.0%) among all four groups. The other three groups of patients had comparable CIR (2-year CIR: group 2 vs. 3 vs. 4, 12.5% vs. 31.3% vs. 22.2%, P > 0.05) and LFS (2-year LFS: group 2 vs. 3 vs. 4, 87.5% vs. 62.5% vs. 66.5%, P > 0.05). Multivariate analysis indicated that disease status (> CR) and pre-MRD were associated with a higher CIR and a lower LFS when patients were classified by pre-MRD and transplant type. Our results suggested that AML patients with FLT3-ITD were able to be separated into high-risk and low-risk relapse groups based on pre-MRD, as determined by multiparameter FCM. Haplo-HSCT might overcome the negative impact of pre-MRD on patient outcomes compared to MSDT. These results require further investigation in prospective study with large numbers of cases.

Coincidence detection in the medial superior olive: mechanistic implications of an analysis of input spiking patterns

PubMed Central

Franken, Tom P.; Bremen, Peter; Joris, Philip X.

2014-01-01

Coincidence detection by binaural neurons in the medial superior olive underlies sensitivity to interaural time difference (ITD) and interaural correlation (ρ). It is unclear whether this process is akin to a counting of individual coinciding spikes, or rather to a correlation of membrane potential waveforms resulting from converging inputs from each side. We analyzed spike trains of axons of the cat trapezoid body (TB) and auditory nerve (AN) in a binaural coincidence scheme. ITD was studied by delaying “ipsi-” vs. “contralateral” inputs; ρ was studied by using responses to different noises. We varied the number of inputs; the monaural and binaural threshold and the coincidence window duration. We examined physiological plausibility of output “spike trains” by comparing their rate and tuning to ITD and ρ to those of binaural cells. We found that multiple inputs are required to obtain a plausible output spike rate. In contrast to previous suggestions, monaural threshold almost invariably needed to exceed binaural threshold. Elevation of the binaural threshold to values larger than 2 spikes caused a drastic decrease in rate for a short coincidence window. Longer coincidence windows allowed a lower number of inputs and higher binaural thresholds, but decreased the depth of modulation. Compared to AN fibers, TB fibers allowed higher output spike rates for a low number of inputs, but also generated more monaural coincidences. We conclude that, within the parameter space explored, the temporal patterns of monaural fibers require convergence of multiple inputs to achieve physiological binaural spike rates; that monaural coincidences have to be suppressed relative to binaural ones; and that the neuron has to be sensitive to single binaural coincidences of spikes, for a number of excitatory inputs per side of 10 or less. These findings suggest that the fundamental operation in the mammalian binaural circuit is coincidence counting of single binaural input spikes. PMID:24822037

The Binaural Interaction Component in Barn Owl (Tyto alba) Presents few Differences to Mammalian Data.

PubMed

Palanca-Castan, Nicolas; Laumen, Geneviève; Reed, Darrin; Köppl, Christine

2016-12-01

The auditory brainstem response (ABR) is an evoked potential that reflects the responses to sound by brainstem neural centers. The binaural interaction component (BIC) is obtained by subtracting the sum of the monaural ABR responses from the binaural response. Its latency and amplitude change in response to variations in binaural cues. The BIC is thus thought to reflect the activity of binaural nuclei and is used to non-invasively test binaural processing. However, any conclusions are limited by a lack of knowledge of the relevant processes at the level of individual neurons. The aim of this study was to characterize the ABR and BIC in the barn owl, an animal where the ITD-processing neural circuits are known in great detail. We recorded ABR responses to chirps and to 1 and 4 kHz tones from anesthetized barn owls. General characteristics of the barn owl ABR were similar to those observed in other bird species. The most prominent peak of the BIC was associated with nucleus laminaris and is thus likely to reflect the known processes of ITD computation in this nucleus. However, the properties of the BIC were very similar to previously published mammalian data and did not reveal any specific diagnostic features. For example, the polarity of the BIC was negative, which indicates a smaller response to binaural stimulation than predicted by the sum of monaural responses. This is contrary to previous predictions for an excitatory-excitatory system such as nucleus laminaris. Similarly, the change in BIC latency with varying ITD was not distinguishable from mammalian data. Contrary to previous predictions, this behavior appears unrelated to the known underlying neural delay-line circuitry. In conclusion, the generation of the BIC is currently inadequately understood and common assumptions about the BIC need to be reconsidered when interpreting such measurements.

Does hemipelvis structure and position influence acetabulum orientation?

PubMed

Musielak, Bartosz; Jóźwiak, Marek; Rychlik, Michał; Chen, Brian Po-Jung; Idzior, Maciej; Grzegorzewski, Andrzej

2016-03-16

Although acetabulum orientation is well established anatomically and radiographically, its relation to the innominate bone has rarely been addressed. If explored, it could open the discussion on patomechanisms of such complex disorders as femoroacetabular impingement (FAI). We therefore evaluated the influence of pelvic bone position and structure on acetabular spatial orientation. We describe this relation and its clinical implications. This retrospective study was based on computed tomography scanning of three-dimensional models of 31 consecutive male pelvises (62 acetabulums). All measurements were based on CT spatial reconstruction with the use of highly specialized software (Rhinoceros). Relations between acetabular orientation (inclination, tilt, anteversion angles) and pelvic structure were evaluated. The following parameters were evaluated to assess the pelvic structure: iliac opening angle, iliac tilt angle, interspinous distance (ISD), intertuberous distance (ITD), height of the pelvis (HP), and the ISD/ITD/HP ratio. The linear and nonlinear dependence of the acetabular angles and hemipelvic measurements were examined with Pearson's product - moment correlation and Spearman's rank correlation coefficient. Correlations different from 0 with p < 0.05 were considered statistically significant. Comparison of the axis position with pelvis structure with orientation in the horizontal plane revealed a significant positive correlation between the acetabular anteversion angle and the iliac opening angle (p = 0.041 and 0.008, respectively). In the frontal plane, there was a positive correlation between the acetabular inclination angle and the iliac tilt angle (p = 0.025 and 0.014, respectively) and the acetabular inclination angle and the ISD/ITD/HP ratio (both p = 0.048). There is a significant correlation of the hemipelvic structure and acetabular orientation under anatomic conditions, especially in the frontal and horizontal planes. In the anteroposterior view, the more tilted-down innominate bone causes a more caudally oriented acetabulum axis, whereas in the horizontal view this relation is reversed. This study may serve as a basis for the discussion on the role of the pelvis in common disorders of the hip.

Monaural and binaural response properties of neurons in the inferior colliculus of the rabbit: effects of sodium pentobarbital.

PubMed

Kuwada, S; Batra, R; Stanford, T R

1989-02-01

1. We studied the effects of sodium pentobarbital on 22 neurons in the inferior colliculus (IC) of the rabbit. We recorded changes in the sensitivity of these neurons to monaural stimulation and to ongoing interaural time differences (ITDs). Monaural stimuli were tone bursts at or near the neuron's best frequency. The ITD was varied by delivering tones that differed by 1 Hz to the two ears, resulting in a 1-Hz binaural beat. 2. We assessed a neuron's ITD sensitivity by calculating three measures from the responses to binaural beats: composite delay, characteristic delay (CD), and characteristic phase (CP). To obtain the composite delay, we first derived period histograms by averaging, showing the response at each stimulating frequency over one period of the beat frequency. Second, the period histograms were replotted as a function of their equivalent interaural delay and then averaged together to yield the composite delay curve. Last, we calculated the composite peak or trough delay by fitting a parabola to the peak or trough of this composite curve. The composite delay curve represents the average response to all frequencies within the neuron's responsive range, and the peak reflects the interaural delay that produces the maximum response. The CD and CP were estimated from a weighted fit of a regression line to the plot of the mean interaural phase of the response versus the stimulating frequency. The slope and phase intercept of this regression line yielded estimates of CD and CP, respectively. These two quantities are thought to reflect the mechanism of ITD sensitivity, which involves the convergence of phase-locked inputs on a binaural cell. The CD estimates the difference in the time required for the two inputs to travel from either ear to this cell, whereas the CP reflects the interaural phase difference of the inputs at this cell. 3. Injections of sodium pentobarbital at subsurgical dosages (less than 25 mg/kg) almost invariably altered the neuron's response rate, response latency, response pattern, and spontaneous activity. Most of these changes were predictable and consistent with an enhancement of inhibitory influences. For example, if the earliest response was inhibitory, later excitation was usually reduced and latency increased. If the earliest response was excitatory, the level of this excitation was unaltered or slightly enhanced, and changes in latency were minimal. 4. The neuron's response pattern also changed in a predictable way. For example, a response with an inhibitory pause could either change to a response with a longer pause or to a response with an onset only.(ABSTRACT TRUNCATED AT 400 WORDS)

The Development of Laminated Armor

DTIC Science & Technology

1948-09-27

U.S. Army Ramie Sea Island Mills, Inc. Ramie-Rayon Sea Island Mills, Ilc. Inconel Fabric (006R260R13) Metal Tex Co. -4- Inconel Fabric (00R21OMl6...Plies .02 U.D. Glass Mat 3111-44 4 Plies .02 IT.D. Glass Mat f 110 90 100 1 Ply Nylon Dusk(13 Oz.) I Ply 00R260R13 2-l/4# Inconel 2 Puiem Nylon Duck(13 Oz...13 Oz.) 1 Ply O07R210M16 2-1/4# Inconel 2 Pl•es Nylon Duck(13 Oz.) I Ply 007R210MI( ?-1/4# Inconel 1 Ply Nylon Duck(13 Oz.) 4 Plies .02 U.D. Mlass Mat

Investigating chaotic features in solar radiation over a tropical station using recurrence quantification analysis

NASA Astrophysics Data System (ADS)

Ogunjo, Samuel T.; Adediji, Adekunle T.; Dada, Joseph B.

2017-01-01

The use of solar energy for power generation and other uses is on the increase. This demand necessitate a better understanding of the underlying dynamics for better prediction. Nonlinear dynamics and its associated tools readily lend itself for such analysis. In this paper, nonlinearity in solar radiation data is tested using recurrence plot (RP) and recurrence quantification analysis (RQA) in a tropical station. The data used was obtained from an ongoing campaign at the Federal University of Technology, Akure, Southwestern Nigeria using an Integrated Sensor Suite (Vantage2 Pro). Half hourly and daily values were tested for each month of the year. Both were found to be nonlinear. The dry months of the year exhibit higher chaoticity compared to the wet months of the year. The daily average values were found to be mildly chaotic. Using RQA, features due to external effects such as harmattan and intertropical discontinuity (ITD) on solar radiation data were uniquely identified.

Software Independent Verification and Validation (SIV&V) Simplified

DTIC Science & Technology

2006-12-01

Configuration Item I/O Input/Output I2V2 Independent Integrated Verification and Validation IBM International Business Machines ICD Interface...IPT Integrated Product Team IRS Interface Requirements Specification ISD Integrated System Diagram ITD Integrated Test Description ITP ...programming languages such as COBOL (Common Business Oriented Language) (Codasyl committee 1960), and FORTRAN (FORmula TRANslator) ( IBM 1952) (Robat 11

Ballet as Somatic Practice: A Case Study Exploring the Integration of Somatic Practices in Ballet Pedagogy

ERIC Educational Resources Information Center

Berg, Tanya

2017-01-01

This case study explores one teacher's integration of Alexander Technique and the work of neuromuscular retrainer Irene Dowd in ballet pedagogy to establish a somatic approach to teaching, learning, and performing ballet technique. This case study highlights the teacher's unique teaching method called IMAGE TECH for dancers (ITD) and offers…

U.S. EPA, Pesticide Product Label, ALL SEASON SPRAYABLE WEED & FEED, 10/04/1991

EPA Pesticide Factsheets

2011-04-21

... ltifo ~tdt~U4:tl\\. "tl(, ~(\\t ~lt:p'.\\ nlr~Ltl) to ""II" 1u '11(';,\\ etf' ~ur·t~(f. "'ilter '\\ r,t,.,Stl1t \\.or to I,'t'd1.,O')1 at «.;~ lr I"" Ir,£ I',tan r II/I: If<1ter .:ar ... • ...

Use of Respiratory Impedance in Prehospital Care of Hypotensive Patients Associated with Hemorrhage and Trauma: A Case Series

DTIC Science & Technology

2012-01-01

Additional patients were included, who had trauma and/or blood loss from Cypress Creek, Texas, and Empress , New York, where the ITD was more recently...respon ders from Lucas County, Ohio, Empress EMS from Yonkers, New York, Eastchester EMS from Eastchester, New York, and Cypress Creek EMS from Spring

Large modal survey testing using the Ibrahim time domain /ITD/ identification technique

NASA Technical Reports Server (NTRS)

Ibrahim, S. R.; Pappa, R. S.

1981-01-01

The ability of the ITD identification algorithm in identifying a complete set of structural modal parameters using a large number of free-response time histories simultaneously in one analysis, assuming a math model with a high number of degrees-of-freedom, has been studied. Identification results using simulated free responses of a uniform rectangular plate, with 225 measurement stations, and experimental responses from a ground vibration test of the Long Duration Exposure Facility (LDEF) Space Shuttle payload, with 142 measurement stations, are presented. As many as 300 degrees-of-freedom were allowed in analyzing these data. In general, the use of a significantly oversized math model in the identification process was found to maintain or increase identification accuracy and to identify modes of low response level that are not identified with smaller math model sizes. The concept of a Mode Shape Correlation Constant is introduced for use when more than one identification analysis of the same structure are conducted. This constant quantifies the degree of correlation between any two sets of complex mode shapes identified using different excitation conditions, different user-selectable algorithm constants, or overlapping sets of measurements.

Computer-guided design, synthesis, and biological evaluation of quinoxalinebisarylureas as FLT3 inhibitors.

PubMed

Göring, Stefan; Bensinger, Dennis; Naumann, Eva C; Schmidt, Boris

2015-03-01

Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in ∼30 % of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Point mutations in the tyrosine kinase domain (TKD) are observed as primary mutations or are acquired as secondary mutations in FLT3 with internal tandem duplications (ITDs) after treatment with tyrosine kinase inhibitors (TKIs). Although dozens of potent inhibitors against FLT3 ITD have been reported, activating TKD point mutations, especially at residues F691 and D835, remain the leading cause for therapy resistance, highlighting the consistent need for new potent inhibitors. Herein we report the identification and characterization of novel quinoxaline-based FLT3 inhibitors. We used the pharmacophore features of diverse known inhibitors as a starting point for a new optimization algorithm for type II TKIs, starting from an in silico library pharmacophore search and induced-fit docking in the known FLT3 structure. This led to the design of a set of diverse quinoxalinebisarylureas, which were profiled in an FLT3 kinase activity assay. The most promising compounds were further evaluated in a zebrafish embryo phenotype assay. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia

PubMed Central

Lee-Sherick, Alisa B.; Zhang, Weihe; Menachof, Kelly K.; Hill, Amanda A.; Rinella, Sean; Kirkpatrick, Gregory; Page, Lauren S.; Stashko, Michael A.; Jordan, Craig T.; Wei, Qi; Liu, Jing; Zhang, Dehui; DeRyckere, Deborah; Wang, Xiaodong; Frye, Stephen; Earp, H. Shelton; Graham, Douglas K.

2015-01-01

Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myeloid leukemia (AML). In this manuscript we describe UNC1666, a novel ATP-competitive small molecule tyrosine kinase inhibitor, which potently diminishes Mer and Flt3 phosphorylation in AML. Treatment with UNC1666 mediated biochemical and functional effects in AML cell lines expressing Mer or Flt3 internal tandem duplication (ITD), including decreased phosphorylation of Mer, Flt3 and downstream effectors Stat, Akt and Erk, induction of apoptosis in up to 98% of cells, and reduction of colony formation by greater than 90%, compared to treatment with vehicle. These effects were dose-dependent, with inhibition of downstream signaling and functional effects correlating with the degree of Mer or Flt3 kinase inhibition. Treatment of primary AML patient samples expressing Mer and/or Flt3-ITD with UNC1666 also inhibited Mer and Flt3 intracellular signaling, induced apoptosis, and inhibited colony formation. In summary, UNC1666 is a novel potent small molecule tyrosine kinase inhibitor that decreases oncogenic signaling and myeloblast survival, thereby validating dual Mer/Flt3 inhibition as an attractive treatment strategy for AML. PMID:25762638

The acoustical bright spot and mislocalization of tones by human listeners.

PubMed

Macaulay, Eric J; Hartmann, William M; Rakerd, Brad

2010-03-01

Listeners attempted to localize 1500-Hz sine tones presented in free field from a loudspeaker array, spanning azimuths from 0 degrees (straight ahead) to 90 degrees (extreme right). During this task, the tone levels and phases were measured in the listeners' ear canals. Because of the acoustical bright spot, measured interaural level differences (ILD) were non-monotonic functions of azimuth with a maximum near 55 degrees . In a source-identification task, listeners' localization decisions closely tracked the non-monotonic ILD, and thus became inaccurate at large azimuths. When listeners received training and feedback, their accuracy improved only slightly. In an azimuth-discrimination task, listeners decided whether a first sound was to the left or to the right of a second. The discrimination results also reflected the confusion caused by the non-monotonic ILD, and they could be predicted approximately by a listener's identification results. When the sine tones were amplitude modulated or replaced by narrow bands of noise, interaural time difference (ITD) cues greatly reduced the confusion for most listeners, but not for all. Recognizing the important role of the bright spot requires a reevaluation of the transition between the low-frequency region for localization (mainly ITD) and the high-frequency region (mainly ILD).

Human Autonomic and Cerebrovascular Responses to Inspiratory Impedance

DTIC Science & Technology

2006-06-01

recorded the ECG, finger photoplethysmographic arterial pressure , cerebral blood flow velocity, and muscle sympathetic nerve activity (MSNA). In a... pressures and R-R intervals, or between arterial pres- sures and cerebral blood flow velocities at the LF (p > 0.05). Conclusions: Our results demonstrate...that the ITD increases arterial pressure , heart rate, and cerebral blood flow velocity independent of changes in autonomic car- diovascular control or

Is It Time to Designate Coast Guard Special Operations Forces

DTIC Science & Technology

2005-06-17

174 Commander Matthew Creelman , USCG Division Chief........................................ 174...February 2005. 9Pailliotet and Phelan. 10Ibid. 11Matthew Creelman , interview by author, Yorktown, VA, 25 January 2005. 12James Perry Stevenson, The $5...doing some research for my master’s thesis at the Army Command and General Staff College. I found out from CDR Creelman that G-CI has ended ITD’s long

IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication.

PubMed

Paschka, Peter; Schlenk, Richard F; Gaidzik, Verena I; Habdank, Marianne; Krönke, Jan; Bullinger, Lars; Späth, Daniela; Kayser, Sabine; Zucknick, Manuela; Götze, Katharina; Horst, Heinz-A; Germing, Ulrich; Döhner, Hartmut; Döhner, Konstanze

2010-08-01

To analyze the frequency and prognostic impact of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations in acute myeloid leukemia (AML). We studied 805 adults (age range, 16 to 60 years) with AML enrolled on German-Austrian AML Study Group (AMLSG) treatment trials AML HD98A and APL HD95 for mutations in exon 4 of IDH1 and IDH2. Patients were also studied for NPM1, FLT3, MLL, and CEBPA mutations. The median follow-up for survival was 6.3 years. IDH mutations were found in 129 patients (16.0%) -IDH1 in 61 patients (7.6%), and IDH2 in 70 patients (8.7%). Two patients had both IDH1 and IDH2 mutations. All but one IDH1 mutation caused substitutions of residue R132; IDH2 mutations caused changes of R140 (n = 48) or R172 (n = 22). IDH mutations were associated with older age (P < .001; effect conferred by IDH2 only); lower WBC (P = .04); higher platelets (P < .001); cytogenetically normal (CN) -AML (P< .001); and NPM1 mutations, in particular with the genotype of mutated NPM1 without FLT3 internal tandem duplication (ITD; P < .001). In patients with CN-AML with the latter genotype, IDH mutations adversely impacted relapse-free survival (RFS; P = .02) and overall survival (P = .03), whereas outcome was not affected in patients with CN-AML who lacked this genotype. In CN-AML, multivariable analyses revealed a significant interaction between IDH mutation and the genotype of mutated NPM1 without FLT3-ITD (ie, the adverse impact of IDH mutation [RFS]; P = .046 was restricted to this patient subset). IDH1 and IDH2 mutations are recurring genetic changes in AML. They constitute a poor prognostic factor in CN-AML with mutated NPM1 without FLT3-ITD, which allows refined risk stratification of this AML subset.

Wilms’ Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study

PubMed Central

Paschka, Peter; Marcucci, Guido; Ruppert, Amy S.; Whitman, Susan P.; Mrózek, Krzysztof; Maharry, Kati; Langer, Christian; Baldus, Claudia D.; Zhao, Weiqiang; Powell, Bayard L.; Baer, Maria R.; Carroll, Andrew J.; Caligiuri, Michael A.; Kolitz, Jonathan E.; Larson, Richard A.; Bloomfield, Clara D.

2008-01-01

Purpose To analyze the prognostic impact of Wilms’ tumor 1 (WT1) gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML). Patients and Methods We studied 196 adults younger than 60 years with newly diagnosed primary CN-AML, who were treated similarly on Cancer and Leukemia Group B (CALGB) protocols 9621 and 19808, for WT1 mutations in exons 7 and 9. The patients also were assessed for the presence of FLT3 internal tandem duplications (FLT3-ITD), FLT3 tyrosine kinase domain mutations (FLT3-TKD), MLL partial tandem duplications (MLL-PTD), NPM1 and CEBPA mutations, and for the expression levels of ERG and BAALC. Results Twenty-one patients (10.7%) harbored WT1 mutations. Complete remission rates were not significantly different between patients with WT1 mutations and those with unmutated WT1 (P = .36; 76% v 84%). Patients with WT1 mutations had worse disease-free survival (DFS; P < .001; 3-year rates, 13% v 50%) and overall survival (OS; P < .001; 3-year rates, 10% v 56%) than patients with unmutated WT1. In multivariable analyses, WT1 mutations independently predicted worse DFS (P = .009; hazard ratio [HR] = 2.7) when controlling for CEBPA mutational status, ERG expression level, and FLT3-ITD/NPM1 molecular-risk group (ie, FLT3-ITDnegative/NPM1mutated as low risk v FLT3-ITDpositive and/or NPM1wild-type as high risk). WT1 mutations also independently predicted worse OS (P < .001; HR = 3.2) when controlling for CEBPA mutational status, FLT3-ITD/NPM1 molecular-risk group, and white blood cell count. Conclusion We report the first evidence that WT1 mutations independently predict extremely poor outcome in intensively treated, younger patients with CN-AML. Future trials should include testing for WT1 mutations as part of molecularly based risk assessment and risk-adapted treatment stratification of patients with CN-AML. PMID:18559874

Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group.

PubMed

Balsat, Marie; Renneville, Aline; Thomas, Xavier; de Botton, Stéphane; Caillot, Denis; Marceau, Alice; Lemasle, Emilie; Marolleau, Jean-Pierre; Nibourel, Olivier; Berthon, Céline; Raffoux, Emmanuel; Pigneux, Arnaud; Rodriguez, Céline; Vey, Norbert; Cayuela, Jean-Michel; Hayette, Sandrine; Braun, Thorsten; Coudé, Marie Magdeleine; Terre, Christine; Celli-Lebras, Karine; Dombret, Hervé; Preudhomme, Claude; Boissel, Nicolas

2017-01-10

Purpose This study assessed the prognostic impact of postinduction NPM1-mutated ( NPM1m) minimal residual disease (MRD) in young adult patients (age, 18 to 60 years) with acute myeloid leukemia, and addressed the question of whether NPM1m MRD may be used as a predictive factor of allogeneic stem cell transplantation (ASCT) benefit. Patients and Methods Among 229 patients with NPM1m who were treated in the Acute Leukemia French Association 0702 (ALFA-0702) trial, MRD evaluation was available in 152 patients in first remission. Patients with nonfavorable AML according to the European LeukemiaNet (ELN) classification were eligible for ASCT in first remission. Results After induction therapy, patients who did not achieve a 4-log reduction in NPM1m peripheral blood-MRD (PB-MRD) had a higher cumulative incidence of relapse (subhazard ratio [SHR], 5.83; P < .001) and a shorter overall survival (OS; hazard ratio [HR], 10.99; P < .001). In multivariable analysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log reduction in PB-MRD were significantly associated with a higher relapse incidence and shorter OS. In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognostic value. In these patients with nonfavorable AML according to European LeukemiaNet, disease-free survival and OS were significantly improved by ASCT in those with a < 4-log reduction in PB-MRD. This benefit was not observed in those with a > 4-log reduction in PB-MRD, with a significant interaction between ASCT effect and PB-MRD response ( P = .024 and .027 for disease-free survival and OS, respectively). Conclusion Our study supports the strong prognostic significance of early NPM1m PB-MRD, independent of the cytogenetic and molecular context. Moreover, NPM1m PB-MRD may be used as a predictive factor for ASCT indication.

Improvements of sound localization abilities by the facial ruff of the barn owl (Tyto alba) as demonstrated by virtual ruff removal.

PubMed

Hausmann, Laura; von Campenhausen, Mark; Endler, Frank; Singheiser, Martin; Wagner, Hermann

2009-11-05

When sound arrives at the eardrum it has already been filtered by the body, head, and outer ear. This process is mathematically described by the head-related transfer functions (HRTFs), which are characteristic for the spatial position of a sound source and for the individual ear. HRTFs in the barn owl (Tyto alba) are also shaped by the facial ruff, a specialization that alters interaural time differences (ITD), interaural intensity differences (ILD), and the frequency spectrum of the incoming sound to improve sound localization. Here we created novel stimuli to simulate the removal of the barn owl's ruff in a virtual acoustic environment, thus creating a situation similar to passive listening in other animals, and used these stimuli in behavioral tests. HRTFs were recorded from an owl before and after removal of the ruff feathers. Normal and ruff-removed conditions were created by filtering broadband noise with the HRTFs. Under normal virtual conditions, no differences in azimuthal head-turning behavior between individualized and non-individualized HRTFs were observed. The owls were able to respond differently to stimuli from the back than to stimuli from the front having the same ITD. By contrast, such a discrimination was not possible after the virtual removal of the ruff. Elevational head-turn angles were (slightly) smaller with non-individualized than with individualized HRTFs. The removal of the ruff resulted in a large decrease in elevational head-turning amplitudes. The facial ruff a) improves azimuthal sound localization by increasing the ITD range and b) improves elevational sound localization in the frontal field by introducing a shift of iso-ILD lines out of the midsagittal plane, which causes ILDs to increase with increasing stimulus elevation. The changes at the behavioral level could be related to the changes in the binaural physical parameters that occurred after the virtual removal of the ruff. These data provide new insights into the function of external hearing structures and open up the possibility to apply the results on autonomous agents, creation of virtual auditory environments for humans, or in hearing aids.

Intrathoracic pressure regulation during cardiopulmonary resuscitation: a feasibility case-series.

PubMed

Segal, Nicolas; Parquette, Brent; Ziehr, Jonathon; Yannopoulos, Demetris; Lindstrom, David

2013-04-01

Intrathoracic pressure regulation (IPR) is a novel, noninvasive therapy intended to increase cardiac output and blood pressure in hypotensive states by generating a negative end expiratory pressure of -12 cm H2O between positive pressure ventilations. In this first feasibility case-series, we tested the hypothesis that IPR improves End tidal (ET) CO2 during cardiopulmonary resuscitation (CPR). ETCO2 was used as a surrogate measure for circulation. All patients were treated initially with manual CPR and an impedance threshold device (ITD). When IPR-trained medics arrived on scene the ITD was removed and an IPR device (CirQLATOR™) was attached to the patient's advanced airway (intervention group). The IPR device lowered airway pressures to -9 mmHg after each positive pressure ventilation for the duration of the expiratory phase. ETCO2, was measured using a capnometer incorporated into the defibrillator system (LifePak™). Values are expressed as mean ± SEM. Results were compared using paired and unpaired Student's t test. p values of <0.05 were considered statistically significant. ETCO2 values in 11 patients in the case series were compared pre and during IPR therapy and also compared to 74 patients in the control group not treated with the new IPR device. ETCO2 values increased from an average of 21 ± 1 mmHg immediately before IPR application to an average value of 32 ± 5 mmHg and to a maximum value of 45 ± 5mmHg during IPR treatment (p<0.001). In the control group ETCO2 values did not change significantly. Return of spontaneous circulation (ROSC) rates were 46% (34/74) with standard CPR and ITD versus 73% (8/11) with standard CPR and the IPR device (p<0.001). ETCO2 levels and ROSC rates were significantly higher in the study intervention group. These findings demonstrate that during CPR circulation may be significantly augmented by generation of a negative end expiratory pressure between each breath. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Using ILD or ITD Cues for Sound Source Localization and Speech Understanding in a Complex Listening Environment by Listeners with Bilateral and with Hearing-Preservation Cochlear Implants

ERIC Educational Resources Information Center

Loiselle, Louise H.; Dorman, Michael F.; Yost, William A.; Cook, Sarah J.; Gifford, Rene H.

2016-01-01

Purpose: To assess the role of interaural time differences and interaural level differences in (a) sound-source localization, and (b) speech understanding in a cocktail party listening environment for listeners with bilateral cochlear implants (CIs) and for listeners with hearing-preservation CIs. Methods: Eleven bilateral listeners with MED-EL…

A Logical Approach to Multilevel Security of Probabilistic Systems

DTIC Science & Technology

1998-01-01

their usefulness in security analysis. Key Words: Formal modeling, Veri cation, Knowledge, Security, Probabilistic Systems Supported by grant HKUST 608...94E from the Hong Kong Research Grants Council. yAuthor for correspondence (syverson@itd.nrl.navy.mil). Supported by ONR. 1 Report Documentation Page...Form ApprovedOMB No. 0704-0188 Public reporting burden for the collection of information is estimated to average 1 hour per response, including the

Testing Experimental Compounds against Leishmaniasis in Laboratory Animal Model Systems.

DTIC Science & Technology

1983-09-01

respiratory chain or pyrimidine biosynthesis. A new compound, alpha difluromethylornithine (RMI 71,782), is a highly specific inhibitor of polyamine...no a;pn-r-nt liff-r-ncp in s’imor-;sion, heli~,or cre when nl crt’ vosu s1 -se lesio)ns w-r- -va-i i-t-d. mai- nln i nbrI f3cmc ro i " iv-r , "ilm-in

Failure of the precedence effect with a noise-band vocoder

PubMed Central

Seeber, Bernhard U.; Hafter, Ervin R.

2011-01-01

The precedence effect (PE) describes the ability to localize a direct, leading sound correctly when its delayed copy (lag) is present, though not separately audible. The relative contribution of binaural cues in the temporal fine structure (TFS) of lead–lag signals was compared to that of interaural level differences (ILDs) and interaural time differences (ITDs) carried in the envelope. In a localization dominance paradigm participants indicated the spatial location of lead–lag stimuli processed with a binaural noise-band vocoder whose noise carriers introduced random TFS. The PE appeared for noise bursts of 10 ms duration, indicating dominance of envelope information. However, for three test words the PE often failed even at short lead–lag delays, producing two images, one toward the lead and one toward the lag. When interaural correlation in the carrier was increased, the images appeared more centered, but often remained split. Although previous studies suggest dominance of TFS cues, no image is lateralized in accord with the ITD in the TFS. An interpretation in the context of auditory scene analysis is proposed: By replacing the TFS with that of noise the auditory system loses the ability to fuse lead and lag into one object, and thus to show the PE. PMID:21428515

The acoustical bright spot and mislocalization of tones by human listeners

PubMed Central

Macaulay, Eric J.; Hartmann, William M.; Rakerd, Brad

2010-01-01

Listeners attempted to localize 1500-Hz sine tones presented in free field from a loudspeaker array, spanning azimuths from 0° (straight ahead) to 90° (extreme right). During this task, the tone levels and phases were measured in the listeners’ ear canals. Because of the acoustical bright spot, measured interaural level differences (ILD) were non-monotonic functions of azimuth with a maximum near 55°. In a source-identification task, listeners’ localization decisions closely tracked the non-monotonic ILD, and thus became inaccurate at large azimuths. When listeners received training and feedback, their accuracy improved only slightly. In an azimuth-discrimination task, listeners decided whether a first sound was to the left or to the right of a second. The discrimination results also reflected the confusion caused by the non-monotonic ILD, and they could be predicted approximately by a listener’s identification results. When the sine tones were amplitude modulated or replaced by narrow bands of noise, interaural time difference (ITD) cues greatly reduced the confusion for most listeners, but not for all. Recognizing the important role of the bright spot requires a reevaluation of the transition between the low-frequency region for localization (mainly ITD) and the high-frequency region (mainly ILD). PMID:20329844

Using individual differences to test the role of temporal and place cues in coding frequency modulation

PubMed Central

Whiteford, Kelly L.; Oxenham, Andrew J.

2015-01-01

The question of how frequency is coded in the peripheral auditory system remains unresolved. Previous research has suggested that slow rates of frequency modulation (FM) of a low carrier frequency may be coded via phase-locked temporal information in the auditory nerve, whereas FM at higher rates and/or high carrier frequencies may be coded via a rate-place (tonotopic) code. This hypothesis was tested in a cohort of 100 young normal-hearing listeners by comparing individual sensitivity to slow-rate (1-Hz) and fast-rate (20-Hz) FM at a carrier frequency of 500 Hz with independent measures of phase-locking (using dynamic interaural time difference, ITD, discrimination), level coding (using amplitude modulation, AM, detection), and frequency selectivity (using forward-masking patterns). All FM and AM thresholds were highly correlated with each other. However, no evidence was obtained for stronger correlations between measures thought to reflect phase-locking (e.g., slow-rate FM and ITD sensitivity), or between measures thought to reflect tonotopic coding (fast-rate FM and forward-masking patterns). The results suggest that either psychoacoustic performance in young normal-hearing listeners is not limited by peripheral coding, or that similar peripheral mechanisms limit both high- and low-rate FM coding. PMID:26627783

Using individual differences to test the role of temporal and place cues in coding frequency modulation.

PubMed

Whiteford, Kelly L; Oxenham, Andrew J

2015-11-01

The question of how frequency is coded in the peripheral auditory system remains unresolved. Previous research has suggested that slow rates of frequency modulation (FM) of a low carrier frequency may be coded via phase-locked temporal information in the auditory nerve, whereas FM at higher rates and/or high carrier frequencies may be coded via a rate-place (tonotopic) code. This hypothesis was tested in a cohort of 100 young normal-hearing listeners by comparing individual sensitivity to slow-rate (1-Hz) and fast-rate (20-Hz) FM at a carrier frequency of 500 Hz with independent measures of phase-locking (using dynamic interaural time difference, ITD, discrimination), level coding (using amplitude modulation, AM, detection), and frequency selectivity (using forward-masking patterns). All FM and AM thresholds were highly correlated with each other. However, no evidence was obtained for stronger correlations between measures thought to reflect phase-locking (e.g., slow-rate FM and ITD sensitivity), or between measures thought to reflect tonotopic coding (fast-rate FM and forward-masking patterns). The results suggest that either psychoacoustic performance in young normal-hearing listeners is not limited by peripheral coding, or that similar peripheral mechanisms limit both high- and low-rate FM coding.

Physiological and content considerations for a second low frequency channel for bass management, subwoofers, and low frequency enhancement (LFE)

NASA Astrophysics Data System (ADS)

Miller, Robert E. (Robin)

2005-04-01

Perception of very low frequencies (VLF) below 125 Hz reproduced by large woofers and subwoofers (SW), encompassing 3 octaves of the 10 regarded as audible, has physiological and content aspects. Large room acoustics and vibrato add VLF fluctuations, modulating audible carrier frequencies to >1 Hz. By convention, sounds below 90 Hz produce no interaural cues useful for spatial perception or localization, therefore bass management redirects the VLF range from main channels to a single (monaural) subwoofer channel, even if to more than one subwoofer. Yet subjects claim they hear a difference between a single subwoofer channel and two (stereo bass). If recordings contain spatial VLF content, is it possible physiologically to perceive interaural time/phase difference (ITD/IPD) between 16 and 125 Hz? To what extent does this perception have a lifelike quality; to what extent is it localization? If a first approximation of localization, would binaural SWs allow a higher crossover frequency (smaller satellite speakers)? Reported research supports the Jeffress model of ITD determination in brain structures, and extending the accepted lower frequency limit of IPD. Meanwhile, uncorrelated very low frequencies exist in all tested multi-channel music and movie content. The audibility, recording, and reproduction of uncorrelated VLF are explored in theory and experiments.

Development of a Heterogeneous sUAS High-Accuracy Positional Flight Data Acquisition System

NASA Technical Reports Server (NTRS)

McSwain, Robert G.; Grosveld, Ferdinand W.

2016-01-01

Recently, a heterogeneous FDAS, consisting of a diverse range of instruments was developed to support acoustic flight research programs at NASA Langley Research Center. In addition to a conventional GPS to measure latitude, longitude and altitude, the FDAS also utilizes a small, light-weight, low-cost DGPS system to obtain centimeter accuracy to measure the distance traveled by sound from a sUAS vehicle to a microphone on the ground. Acoustic flight testing using the FDAS installed on several different sUAS platforms has been conducted in support of the NASA CAS DELIVER and ERA ITD projects (Reference 1). The first FDAS prototype was assembled and implemented in the acoustic/flight measurement system in December 2014 to support DELIVER acoustic flight tests. Evaluation of the system performance and results from the data analyses were used to further test, develop and enhance the FDAS over a six-month period to support acoustic flight research for the ERA.

A Steganographic Embedding Undetectable by JPEG Compatibility Steganalysis

DTIC Science & Technology

2002-01-01

itd.nrl.navy.mil Abstract. Steganography and steganalysis of digital images is a cat- and-mouse game. In recent work, Fridrich, Goljan and Du introduced a method...proposed embedding method. 1 Introduction Steganography and steganalysis of digital images is a cat-and-mouse game. Ever since Kurak and McHugh’s seminal...paper on LSB embeddings in images [10], various researchers have published work on either increasing the payload, im- proving the resistance to

A Calculus of Macro-Events: Progress Report

DTIC Science & Technology

2000-01-01

1410, USA iliano@itd.nrl.navy.mil Angelo Montanari Dipartimento di Matematica e Informatica Universita di Udine Via delle Scienze, 206 { 33100 Udine...and process iteration. This proposal builds on work by Chittaro and Montanari [10] on mod- eling discrete processes. The set of constructors of the...situations, in many cases the occurrence of an event happens over a period of time [24]. Capturing this possibility enables ner mod- els , as we can now

Acute myeloid leukaemia with myelodysplastic features in children: a report of Japanese Paediatric Leukaemia/Lymphoma Study Group.

PubMed

Kinoshita, Akitoshi; Miyachi, Hayato; Matsushita, Hiromichi; Yabe, Miharu; Taki, Tomohiko; Watanabe, Tomoyuki; Saito, Akiko M; Tomizawa, Daisuke; Taga, Takashi; Takahashi, Hiroyuki; Matsuo, Hidemasa; Kodama, Kumi; Ohki, Kentaro; Hayashi, Yasuhide; Tawa, Akio; Horibe, Keizo; Adachi, Souichi

2014-10-01

The clinical characteristics and prognostic relevance of acute myeloid leukaemia (AML) with myelodysplastic features remains to be clarified in children. We prospectively examined 443 newly diagnosed patients in a multicentre clinical trial for paediatric de novo AML, and found 'AML with myelodysplasia-related changes' (AML-MRC) according to the 2008 World Health Organization classification in 93 (21·0%), in whom 59 were diagnosed from myelodysplasia-related cytogenetics alone, 28 from multilineage dysplasia alone and six from a combination of both. Compared with 111 patients with 'AML, not otherwise specified' (AML-NOS), patients with 'AML-MRC' presented at a younger age, with a lower white blood cell count, higher incidence of 20-30% bone marrow blasts, unfavourable cytogenetics and a lower frequency of Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD), NPM1 and CEBPA mutations. Complete remission rate and 3-year probability of event-free survival were significantly worse in 'AML-MRC' patients (67·7 vs. 85·6%, P < 0·01, 37·1% vs. 53·8%, P = 0·02, respectively), but 3-year overall survival and relapse-free survival were comparable with 'AML-NOS' patients. By multivariate analysis, FLT3-ITD was solely associated with worse overall survival. These results support the distinctive features of the category 'AML-MRC' even in children. © 2014 John Wiley & Sons Ltd.

Underwater localization of pure tones by harbor seals (Phoca vitulina).

PubMed

Bodson, Anaïs; Miersch, Lars; Dehnhardt, Guido

2007-10-01

The underwater sound localization acuity of harbor seals (Phoca vitulina) was measured in the horizontal plane. Minimum audible angles (MAAs) of pure tones were determined as a function of frequency from 0.2 to 16 kHz for two seals. Testing was conducted in a 10-m-diam underwater half circle using a right/left psychophysical procedure. The results indicate that for both harbor seals, MAAs were large at high frequencies (13.5 degrees and 17.4 degrees at 16 kHz), transitional at intermediate frequencies (9.6 degrees and 10.1 degrees at 4 kHz), and particularly small at low frequencies (3.2 degrees and 3.1 degrees at 0.2 kHz). Harbor seals seem to be able to utilize both binaural cues, interaural time differences (ITDs) and interaural intensity differences (IIDs), but a significant decrease in the sound localization acuity with increasing frequency suggests that IID cues may not be as robust as ITD cues under water. These results suggest that the harbor seal can be regarded as a low-frequency specialist. Additionally, to obtain a MAA more representative of the species, the horizontal underwater MAA of six adult harbor seals was measured at 2 kHz under identical conditions. The MAAs of the six animals ranged from 8.8 degrees to 11.7 degrees , resulting in a mean MAA of 10.3 degrees .

Radiometric Measurements by the MIDAS III System at Key West. Volume I. Cloud Backgrounds.

DTIC Science & Technology

1979-09-01

13 13.3 System Relative Spectral Response - Filter No. 2 5(4.4-4.77 pim ) ............................................. 14 3.4 System Relative Spectral...Response - Filter No. 5 (3.8-4.2 pim ) .............................................. 15 3.5 System Relative Spectral Response - Filter No. 6 (3.4-4.3...5 dat a was recorded dirtxet l ott t he recordinig osc ml logrtt1 Witereis tilt- 8-13 data was recorded on t tiet I ape, recorders i xst itd laxter p

The Shock and Vibration Bulletin. Part 3. Machinery Dynamics, System Identification and Structural Analysis

DTIC Science & Technology

1985-06-01

purposes. 55 15 525 + 2 225L L53 + L3 ) + 2G3(L 2 + L35L4 + L45)" For the present system identification + 2G(L45 2 + L45L5 + L5 "L 1 technique, the...orbital model is comprised of 257 nodes and 819 dynamic:"DOF’s. k; were compared to ITD results for a wide variety of TD input parameters. Overall, the

Genetic disorders of the anterior pituitary gland.

PubMed

Teller, W M

1985-01-01

This survey deals with disorders caused by genetically disturbed function of the anterior pituitary gland. Genetic Dwarfism may be caused by isolated growth hormone deficiency (IGHD) or panpituitary diseases, such as congenital absence of the pituitary or familial panhypopituitarism. Genetic disturbances of isolated pituitary hormone secretion without dwarfism may occur as isolated gonadotropin deficiency (IGD), isolated luteinizing hormone deficiency ("fertile eunuch"), Kallmann syndrome (olfactogenital dysplasia), isolated thyrotropin deficiency (ITD) and isolated corticotropin deficiency (ICD). Pituitary dysfunction may also be associated with other genetic disease entities.

Digital Database of Selected Aggregate and Related Resources in Ada, Boise, Canyon, Elmore, Gem, and Owyhee Counties, Southwestern Idaho

USGS Publications Warehouse

Moyle, Phillip R.; Wallis, John C.; Bliss, James D.; Bolm, Karen D.

2004-01-01

The U.S. Geological Survey (USGS) compiled a database of aggregate sites and geotechnical sample data for six counties - Ada, Boise, Canyon, Elmore, Gem, and Owyhee - in southwest Idaho as part of a series of studies in support of the Bureau of Land Management (BLM) planning process. Emphasis is placed on sand and gravel sites in deposits of the Boise River, Snake River, and other fluvial systems and in Neogene lacustrine deposits. Data were collected primarily from unpublished Idaho Transportation Department (ITD) records and BLM site descriptions, published Army Corps of Engineers (ACE) records, and USGS sampling data. The results of this study provides important information needed by land-use planners and resource managers, particularly in the BLM, to anticipate and plan for demand and development of sand and gravel and other mineral material resources on public lands in response to the urban growth in southwestern Idaho.

Maintenance lenalidomide in combination with 5-azacitidine as post-remission therapy for acute myeloid leukaemia.

PubMed

Wei, Andrew; Tan, Peter; Perruzza, Sarah; Govindaraj, Chindu; Fleming, Shaun; McManus, Julie; Avery, Sharon; Patil, Sushrut; Stevenson, William; Plebanski, Magdalena; Spencer, Andrew

2015-04-01

In this Phase 1b study, the safety and tolerability of maintenance therapy, comprising lenalidomide (0-25 mg, days 5-25) in combination with azacitidine (50-75 mg/m(2) , days 1-5) every 28 d, was explored in 40 patients with acute myeloid leukaemia (AML) in complete remission after chemotherapy. Eligibility included AML in first complete remission (CR1) with adverse risk karyotype (n = 8), fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) (n = 5), age ≥60 years (n = 31) or AML in second remission (CR2) (n = 14). Dose-limiting toxicity was not reached. Common toxicities were haematological, infection, injection pain, constipation, fatigue and diarrhoea. In CR1, median relapse-free (RFS) and overall survival (OS) was 12 and 20 months, respectively. In CR2, median RFS was 11 months, with median OS not yet reached. Among 29 patients with intermediate cytogenetic risk, RFS was 50% at 24 months. There were five patients with concomitant FLT3-ITD and nucleophosmin (NPM1) mutation; none have relapsed and all are still alive after 17-39 months. Maintenance lenalidomide/azacitidine augmented the function of cytotoxic T lymphocytes, particularly in patients with NPM1 mutation. The lenalidomide/azacitidine maintenance combination was effective in suppressing residual DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A)-positive disease, resulting in sustained remission in patients with concurrent NPM1 mutation. Azacitidine/lenalidomide as maintenance therapy for high-risk AML warrants further exploration. © 2015 John Wiley & Sons Ltd.

Theoretical foundations of the sound analog membrane potential that underlies coincidence detection in the barn owl

PubMed Central

Ashida, Go; Funabiki, Kazuo; Carr, Catherine E.

2013-01-01

A wide variety of neurons encode temporal information via phase-locked spikes. In the avian auditory brainstem, neurons in the cochlear nucleus magnocellularis (NM) send phase-locked synaptic inputs to coincidence detector neurons in the nucleus laminaris (NL) that mediate sound localization. Previous modeling studies suggested that converging phase-locked synaptic inputs may give rise to a periodic oscillation in the membrane potential of their target neuron. Recent physiological recordings in vivo revealed that owl NL neurons changed their spike rates almost linearly with the amplitude of this oscillatory potential. The oscillatory potential was termed the sound analog potential, because of its resemblance to the waveform of the stimulus tone. The amplitude of the sound analog potential recorded in NL varied systematically with the interaural time difference (ITD), which is one of the most important cues for sound localization. In order to investigate the mechanisms underlying ITD computation in the NM-NL circuit, we provide detailed theoretical descriptions of how phase-locked inputs form oscillating membrane potentials. We derive analytical expressions that relate presynaptic, synaptic, and postsynaptic factors to the signal and noise components of the oscillation in both the synaptic conductance and the membrane potential. Numerical simulations demonstrate the validity of the theoretical formulations for the entire frequency ranges tested (1–8 kHz) and potential effects of higher harmonics on NL neurons with low best frequencies (<2 kHz). PMID:24265616

Mutation profiling of 16 candidate genes in de novo acute myeloid leukemia patients.

PubMed

Zhang, Yang; Wang, Fang; Chen, Xue; Liu, Wenjing; Fang, Jiancheng; Wang, Mingyu; Teng, Wen; Cao, Panxiang; Liu, Hongxing

2018-05-26

This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in de novo acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of de novo AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing.We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. FLT3-ITD was the most common mutated gene (16.2%, 42/259), followed by CEBPA (15.1%, 39/259), NRAS (14.7%, 38/259), and NPM1 (13.5%, 35/259). Concurrence was observed in 97.1% of the NPM1 mutated cases and in 29.6% of the double mutated CEBPA cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the IDH2 gene: R140 mutations were associated with NPM1 and/or FLT3-ITD mutations, whereas R172 mutations co-occurred with DNMT3A mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with NPM1 mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.

Interactions between auditory 'what' and 'where' pathways revealed by enhanced near-threshold discrimination of frequency and position.

PubMed

Tardif, Eric; Spierer, Lucas; Clarke, Stephanie; Murray, Micah M

2008-03-07

Partially segregated neuronal pathways ("what" and "where" pathways, respectively) are thought to mediate sound recognition and localization. Less studied are interactions between these pathways. In two experiments, we investigated whether near-threshold pitch discrimination sensitivity (d') is altered by supra-threshold task-irrelevant position differences and likewise whether near-threshold position discrimination sensitivity is altered by supra-threshold task-irrelevant pitch differences. Each experiment followed a 2 x 2 within-subjects design regarding changes/no change in the task-relevant and task-irrelevant stimulus dimensions. In Experiment 1, subjects discriminated between 750 Hz and 752 Hz pure tones, and d' for this near-threshold pitch change significantly increased by a factor of 1.09 when accompanied by a task-irrelevant position change of 65 micros interaural time difference (ITD). No response bias was induced by the task-irrelevant position change. In Experiment 2, subjects discriminated between 385 micros and 431 micros ITDs, and d' for this near-threshold position change significantly increased by a factor of 0.73 when accompanied by task-irrelevant pitch changes (6 Hz). In contrast to Experiment 1, task-irrelevant pitch changes induced a response criterion bias toward responding that the two stimuli differed. The collective results are indicative of facilitative interactions between "what" and "where" pathways. By demonstrating how these pathways may cooperate under impoverished listening conditions, our results bear implications for possible neuro-rehabilitation strategies. We discuss our results in terms of the dual-pathway model of auditory processing.

A model of head-related transfer functions based on a state-space analysis

NASA Astrophysics Data System (ADS)

Adams, Norman Herkamp

This dissertation develops and validates a novel state-space method for binaural auditory display. Binaural displays seek to immerse a listener in a 3D virtual auditory scene with a pair of headphones. The challenge for any binaural display is to compute the two signals to supply to the headphones. The present work considers a general framework capable of synthesizing a wide variety of auditory scenes. The framework models collections of head-related transfer functions (HRTFs) simultaneously. This framework improves the flexibility of contemporary displays, but it also compounds the steep computational cost of the display. The cost is reduced dramatically by formulating the collection of HRTFs in the state-space and employing order-reduction techniques to design efficient approximants. Order-reduction techniques based on the Hankel-operator are found to yield accurate low-cost approximants. However, the inter-aural time difference (ITD) of the HRTFs degrades the time-domain response of the approximants. Fortunately, this problem can be circumvented by employing a state-space architecture that allows the ITD to be modeled outside of the state-space. Accordingly, three state-space architectures are considered. Overall, a multiple-input, single-output (MISO) architecture yields the best compromise between performance and flexibility. The state-space approximants are evaluated both empirically and psychoacoustically. An array of truncated FIR filters is used as a pragmatic reference system for comparison. For a fixed cost bound, the state-space systems yield lower approximation error than FIR arrays for D>10, where D is the number of directions in the HRTF collection. A series of headphone listening tests are also performed to validate the state-space approach, and to estimate the minimum order N of indiscriminable approximants. For D = 50, the state-space systems yield order thresholds less than half those of the FIR arrays. Depending upon the stimulus uncertainty, a minimum state-space order of 7≤N≤23 appears to be adequate. In conclusion, the proposed state-space method enables a more flexible and immersive binaural display with low computational cost.

Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors.

PubMed

Antonescu, Cristina R; Sommer, Gunhild; Sarran, Lisa; Tschernyavsky, Sylvia J; Riedel, Elyn; Woodruff, James M; Robson, Mark; Maki, Robert; Brennan, Murray F; Ladanyi, Marc; DeMatteo, Ronald P; Besmer, Peter

2003-08-15

Activating mutations of the KIT juxtamembrane region are the most common genetic events in gastrointestinal stromal tumors (GISTs) and have been noted as independent prognostic factors. The impact of KIT mutation in other regions, such as the extracellular or kinase domains, is not well-defined and fewer than 30 cases have been published to date. One hundred twenty GISTs, confirmed by KIT immunoreactivity, were evaluated for the presence of KIT exon 9, 11, 13, and 17 mutations. The relation between the presence/type of KIT mutation and clinicopathological factors was analyzed using Fisher's exact test and log-rank test. Forty-four % of the tumors were located in the stomach, 47% in the small bowel, 6% in the rectum, and 3% in the retroperitoneum. Overall, KIT mutations were detected in 78% of patients as follows: 67% in exon 11, 11% in exon 9, and none in exon 13 or 17. The types of KIT exon 11 mutations were heterogeneous and clustered in the classic "hot spot" at the 5' end of exon 11. Seven % of cases showed internal tandem duplications (ITD) at the 3' end of exon 11, in a region that we designate as a second hot spot for KIT mutations. Interestingly, these cases were associated with: female predominance, stomach location, occurrence in older patients, and favorable outcome. There were significant associations between exon 9 mutations and large tumor size (P < 0.001) and extragastric location (P = 0.02). Ten of these 13 patients with more than 1-year follow-up have developed recurrent disease. Most KIT-expressing GISTs show KIT mutations that are preferentially located within the classic hot spot of exon 11. In addition, we found an association between a second hot spot at the 3'end of exon 11, characterized by ITDs, and a subgroup of clinically indolent gastric GISTs in older females. KIT exon 9 mutations seem to define a distinct subset of GISTs, located predominantly in the small bowel and associated with an unfavorable clinical course.

The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow

PubMed Central

Lange, Janusz; Dworacki, Grzegorz; Nowak, Dorota; Simiczyjew, Aleksandra; Mordak-Domagala, Monika; Sedzimirska, Mariola

2018-01-01

We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia. The patients (i) responded to the treatment with cessation of blasts which lasted 1, 17 and 42+ months, (ii) developed skin lesions with CD3+ cell invasion of the epidermis, (iii) had marrow infiltrated with CD8+ lymphocytes which co-expressed PD-1 (programmed cell death protein 1 receptor, CD279) in higher proportions than those in the blood (163±32 x103 cells/μl vs 38±8 x103 cells/μl, p<0.001). The Lymphoprep fraction of marrow cells investigated for the expression of genes involved in lymphocyte activation showed in the patients with long lasting complete remission (CR) a similar pattern characterized by (i) a low expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) as well as that of angiopoietin-like 4 (ANGPTL4) (supporting the immune response and anti-angiogenic) genes, and (ii) higher expression of fibroblast growth factor 1 (FGF1) and collagen type IV alpha 3 chain (COL4A3) as well as toll like receptor 9 (TLR9) and interleukin-12 (IL-12) (pro-inflammatory expression profile) genes as compared with the normal individual. The positive effect in one patient hardly justified the presence of unwanted effects (progressive chronic graft-versus-host disease (cGvHD) and avascular necrosis of the femur), which were in contrast negligible in the other patient. The anti-leukemic and unwanted effects of sorafenib do not rely on each other. PMID:29304116

The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML

PubMed Central

Novotny-Diermayr, V; Hart, S; Goh, K C; Cheong, A; Ong, L-C; Hentze, H; Pasha, M K; Jayaraman, R; Ethirajulu, K; Wood, J M

2012-01-01

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2V617F mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2V617F mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations. PMID:22829971

Neuromagnetic recordings reveal the temporal dynamics of auditory spatial processing in the human cortex.

PubMed

Tiitinen, Hannu; Salminen, Nelli H; Palomäki, Kalle J; Mäkinen, Ville T; Alku, Paavo; May, Patrick J C

2006-03-20

In an attempt to delineate the assumed 'what' and 'where' processing streams, we studied the processing of spatial sound in the human cortex by using magnetoencephalography in the passive and active recording conditions and two kinds of spatial stimuli: individually constructed, highly realistic spatial (3D) stimuli and stimuli containing interaural time difference (ITD) cues only. The auditory P1m, N1m, and P2m responses of the event-related field were found to be sensitive to the direction of sound source in the azimuthal plane. In general, the right-hemispheric responses to spatial sounds were more prominent than the left-hemispheric ones. The right-hemispheric P1m and N1m responses peaked earlier for sound sources in the contralateral than for sources in the ipsilateral hemifield and the peak amplitudes of all responses reached their maxima for contralateral sound sources. The amplitude of the right-hemispheric P2m response reflected the degree of spatiality of sound, being twice as large for the 3D than ITD stimuli. The results indicate that the right hemisphere is specialized in the processing of spatial cues in the passive recording condition. Minimum current estimate (MCE) localization revealed that temporal areas were activated both in the active and passive condition. This initial activation, taking place at around 100 ms, was followed by parietal and frontal activity at 180 and 200 ms, respectively. The latter activations, however, were specific to attentional engagement and motor responding. This suggests that parietal activation reflects active responding to a spatial sound rather than auditory spatial processing as such.

Response Properties of Neighboring Neurons in the Auditory Midbrain for Pure-Tone Stimulation: A Tetrode Study

PubMed Central

Seshagiri, Chandran V.; Delgutte, Bertrand

2007-01-01

The complex anatomical structure of the central nucleus of the inferior colliculus (ICC), the principal auditory nucleus in the midbrain, may provide the basis for functional organization of auditory information. To investigate this organization, we used tetrodes to record from neighboring neurons in the ICC of anesthetized cats and studied the similarity and difference among the responses of these neurons to pure-tone stimuli using widely used physiological characterizations. Consistent with the tonotopic arrangement of neurons in the ICC and reports of a threshold map, we found a high degree of correlation in the best frequencies (BFs) of neighboring neurons, which were mostly <3 kHz in our sample, and the pure-tone thresholds among neighboring neurons. However, width of frequency tuning, shapes of the frequency response areas, and temporal discharge patterns showed little or no correlation among neighboring neurons. Because the BF and threshold are measured at levels near the threshold and the characteristic frequency (CF), neighboring neurons may receive similar primary inputs tuned to their CF; however, at higher levels, additional inputs from other frequency channels may be recruited, introducing greater variability in the responses. There was also no correlation among neighboring neurons' sensitivity to interaural time differences (ITD) measured with binaural beats. However, the characteristic phases (CPs) of neighboring neurons revealed a significant correlation. Because the CP is related to the neural mechanisms generating the ITD sensitivity, this result is consistent with segregation of inputs to the ICC from the lateral and medial superior olives. PMID:17671101

Response properties of neighboring neurons in the auditory midbrain for pure-tone stimulation: a tetrode study.

PubMed

Seshagiri, Chandran V; Delgutte, Bertrand

2007-10-01

The complex anatomical structure of the central nucleus of the inferior colliculus (ICC), the principal auditory nucleus in the midbrain, may provide the basis for functional organization of auditory information. To investigate this organization, we used tetrodes to record from neighboring neurons in the ICC of anesthetized cats and studied the similarity and difference among the responses of these neurons to pure-tone stimuli using widely used physiological characterizations. Consistent with the tonotopic arrangement of neurons in the ICC and reports of a threshold map, we found a high degree of correlation in the best frequencies (BFs) of neighboring neurons, which were mostly <3 kHz in our sample, and the pure-tone thresholds among neighboring neurons. However, width of frequency tuning, shapes of the frequency response areas, and temporal discharge patterns showed little or no correlation among neighboring neurons. Because the BF and threshold are measured at levels near the threshold and the characteristic frequency (CF), neighboring neurons may receive similar primary inputs tuned to their CF; however, at higher levels, additional inputs from other frequency channels may be recruited, introducing greater variability in the responses. There was also no correlation among neighboring neurons' sensitivity to interaural time differences (ITD) measured with binaural beats. However, the characteristic phases (CPs) of neighboring neurons revealed a significant correlation. Because the CP is related to the neural mechanisms generating the ITD sensitivity, this result is consistent with segregation of inputs to the ICC from the lateral and medial superior olives.

High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study

PubMed Central

Langer, Christian; Radmacher, Michael D.; Ruppert, Amy S.; Whitman, Susan P.; Paschka, Peter; Mrózek, Krzysztof; Baldus, Claudia D.; Vukosavljevic, Tamara; Liu, Chang-Gong; Ross, Mary E.; Powell, Bayard L.; de la Chapelle, Albert; Kolitz, Jonathan E.; Larson, Richard A.; Marcucci, Guido

2008-01-01

BAALC expression is considered an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML), but has yet to be investigated together with multiple other established prognostic molecular markers in CN-AML. We analyzed BAALC expression in 172 primary CN-AML patients younger than 60 years of age, treated similarly on CALGB protocols. High BAALC expression was associated with FLT3-ITD (P = .04), wild-type NPM1 (P < .001), mutated CEBPA (P = .003), MLL-PTD (P = .009), absent FLT3-TKD (P = .005), and high ERG expression (P = .05). In multivariable analysis, high BAALC expression independently predicted lower complete remission rates (P = .04) when adjusting for ERG expression and age, and shorter survival (P = .04) when adjusting for FLT3-ITD, NPM1, CEBPA, and white blood cell count. A gene-expression signature of 312 probe sets differentiating high from low BAALC expressers was identified. High BAALC expression was associated with overexpression of genes involved in drug resistance (MDR1) and stem cell markers (CD133, CD34, KIT). Global microRNA-expression analysis did not reveal significant differences between BAALC expression groups. However, an analysis of microRNAs that putatively target BAALC revealed a potentially interesting inverse association between expression of miR-148a and BAALC. We conclude that high BAALC expression is an independent adverse prognostic factor and is associated with a specific gene-expression profile. PMID:18378853

Isolation of sabin-like polioviruses from wastewater in a country using inactivated polio vaccine.

PubMed

Zurbriggen, Sebastian; Tobler, Kurt; Abril, Carlos; Diedrich, Sabine; Ackermann, Mathias; Pallansch, Mark A; Metzler, Alfred

2008-09-01

From 2001 to 2004, Switzerland switched from routine vaccination with oral polio vaccine (OPV) to inactivated polio vaccine (IPV), using both vaccines in the intervening period. Since IPV is less effective at inducing mucosal immunity than OPV, this change might allow imported poliovirus to circulate undetected more easily in an increasingly IPV-immunized population. Environmental monitoring is a recognized tool for identifying polioviruses in a community. To look for evidence of poliovirus circulation following cessation of OPV use, two sewage treatment plants located in the Zurich area were sampled from 2004 to 2006. Following virus isolation using either RD or L20B cells, enteroviruses and polioviruses were identified by reverse transcription-PCR. A total of 20 out of 174 wastewater samples were positive for 62 Sabin-like isolates. One isolate from each poliovirus-positive sample was analyzed in more detail. Sequencing the complete viral protein 1 (VP1) capsid coding region, as well as intratypic differentiation (ITD), identified 3 Sabin type 1, 13 Sabin type 2, and 4 Sabin type 3 strains. One serotype 1 strain showed a discordant result in the ITD. Three-quarters of the strains showed mutations within the 5' untranslated region and VP1, known to be associated with reversion to virulence. Moreover, three strains showed heterotypic recombination (S2/S1 and S3/S2/S3). The low number of synonymous mutations and the partial temperature sensitivity are not consistent with extended circulation of these Sabin virus strains. Nevertheless, the continuous introduction of polioviruses into the community emphasizes the necessity for uninterrupted child vaccination to maintain high herd immunity.

Influence of aging on human sound localization

PubMed Central

Dobreva, Marina S.; O'Neill, William E.

2011-01-01

Errors in sound localization, associated with age-related changes in peripheral and central auditory function, can pose threats to self and others in a commonly encountered environment such as a busy traffic intersection. This study aimed to quantify the accuracy and precision (repeatability) of free-field human sound localization as a function of advancing age. Head-fixed young, middle-aged, and elderly listeners localized band-passed targets using visually guided manual laser pointing in a darkened room. Targets were presented in the frontal field by a robotically controlled loudspeaker assembly hidden behind a screen. Broadband targets (0.1–20 kHz) activated all auditory spatial channels, whereas low-pass and high-pass targets selectively isolated interaural time and intensity difference cues (ITDs and IIDs) for azimuth and high-frequency spectral cues for elevation. In addition, to assess the upper frequency limit of ITD utilization across age groups more thoroughly, narrowband targets were presented at 250-Hz intervals from 250 Hz up to ∼2 kHz. Young subjects generally showed horizontal overestimation (overshoot) and vertical underestimation (undershoot) of auditory target location, and this effect varied with frequency band. Accuracy and/or precision worsened in older individuals for broadband, high-pass, and low-pass targets, reflective of peripheral but also central auditory aging. In addition, compared with young adults, middle-aged, and elderly listeners showed pronounced horizontal localization deficiencies (imprecision) for narrowband targets within 1,250–1,575 Hz, congruent with age-related central decline in auditory temporal processing. Findings underscore the distinct neural processing of the auditory spatial cues in sound localization and their selective deterioration with advancing age. PMID:21368004

Fragment length analysis screening for detection of CEBPA mutations in intermediate-risk karyotype acute myeloid leukemia.

PubMed

Fuster, Oscar; Barragán, Eva; Bolufer, Pascual; Such, Esperanza; Valencia, Ana; Ibáñez, Mariam; Dolz, Sandra; de Juan, Inmaculada; Jiménez, Antonio; Gómez, Maria Teresa; Buño, Ismael; Martínez, Joaquín; Cervera, José; Montesinos, Pau; Moscardó, Federico; Sanz, Miguel Ángel

2012-01-01

During last years, molecular markers have been increased as prognostic factors routinely screened in acute myeloid leukemia (AML). Recently, an increasing interest has been reported in introducing to clinical practice screening for mutations in the CCAAT/enhancer-binding protein α (CEBPA) gene in AML, as it seems to be a good prognostic factor. However, there is no reliable established method for assessing CEBPA mutations during the diagnostic work-up of AMLs. We describe here a straightforward and reliable fragment analysis method based in PCR capillary electrophoresis (PCR-CE) for screening of CEBPA mutations; moreover, we present the results obtained in 151 intermediate-risk karyotype AML patients (aged 16-80 years). The method gave a specificity of 100% and sensitivity of 93% with a lower detection limit of 1-5% for CEBPA mutations. The series found 19 mutations and four polymorphisms in 12 patients, seven of whom (58%) presented two mutations. The overall frequency of CEBPA mutations in AML was 8% (n = 12). CEBPA mutations showed no coincidence with FLT3-ITD or NPM1 mutations. CEBPA mutation predicted better disease-free survival in the group of patients without FLT3-ITD, NPM, or both genes mutated (HR 3.6, IC 95%; 1.0-13.2, p = 0.05) and better overall survival in patients younger than 65 of this group without molecular markers (HR 4.0, IC 95%; 1.0-17.4, p = 0.05). In conclusion, the fragment analysis method based in PCR-CE is a rapid, specific, and sensitive method for CEBPA mutation screening and our results confirm that CEBPA mutations can identify a subgroup of patients with favorable prognosis in AML with intermediate-risk karyotype.

Use of Wilms Tumor 1 Gene Expression as a Reliable Marker for Prognosis and Minimal Residual Disease Monitoring in Acute Myeloid Leukemia With Normal Karyotype Patients.

PubMed

Marjanovic, Irena; Karan-Djurasevic, Teodora; Ugrin, Milena; Virijevic, Marijana; Vidovic, Ana; Tomin, Dragica; Suvajdzic Vukovic, Nada; Pavlovic, Sonja; Tosic, Natasa

2017-05-01

Acute myeloid leukemia with normal karyotype (AML-NK) represents the largest group of AML patients classified with an intermediate prognosis. A constant need exists to introduce new molecular markers for more precise risk stratification and for minimal residual disease (MRD) monitoring. Quantitative assessment of Wilms tumor 1 (WT1) gene transcripts was performed using real-time polymerase chain reaction. The bone marrow samples were collected at the diagnosis from 104 AML-NK patients and from 34 of these patients during follow-up or disease relapse. We found that overexpression of the WT1 gene (WT1 high status), present in 25.5% of patients, was an independent unfavorable factor for achieving complete remission. WT1 high status was also associated with resistance to therapy and shorter disease-free survival and overall survival. Assessment of the log reduction value of WT1 expression, measured in paired diagnosis/complete remission samples, revealed that patients with a log reduction of < 2 had a tendency toward shorter disease-free survival and overall survival and a greater incidence of disease relapse. Combining WT1 gene expression status with NPM1 and FLT3-ITD mutational status, we found that the tumor behavior of intermediate patients (FLT3-ITD - /NPM1 - double negative) with WT1 high status is almost the same as the tumor behavior of the adverse risk group. WT1 expression status represents a good molecular marker of prognosis, response to treatment, and MRD monitoring. Above all, the usage of the WT1 expression level as an additional marker for more precise risk stratification of AML-NK patients could lead to more adapted, personalized treatment protocols. Copyright © 2017 Elsevier Inc. All rights reserved.

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long-term analysis of the ALFA-9802 GM-CSF study.

PubMed

Thomas, Xavier; Raffoux, Emmanuel; Renneville, Aline; Pautas, Cecile; de Botton, Stephane; Terre, Christine; Gardin, Claude; Hayette, Sandrine; Preudhomme, Claude; Dombret, Herve

2010-04-01

: Priming with granulocytic hematopoietic growth factors may modulate cell cycle kinetics of leukemic cells and render them more susceptible to phase-specific chemotherapeutic agents. In a first report, we have shown that priming with granulocyte-macrophage colony-stimulating factor (GM-CSF) may enhance complete remission (CR) rate and event-free survival (EFS) in younger adults with acute myeloid leukemia (AML). : In this randomized trial, 259 patients with AML were randomized at baseline to receive or not receive GM-CSF concurrently with all cycles of chemotherapy. The effects of GM-CSF on survival were reported herein with a long-term follow-up and studied according to distinct biological subgroups defined on cytogenetics and molecular markers. : The EFS rate was better in the GM-CSF group (43% vs 34%; P = .04). GM-CSF did not improve the outcome in patients from good risk subgroups, while patients from poor risk subgroups benefited from GM-CSF therapy. In this population, the difference in terms of EFS probability was mainly observed in patients with high initial white blood cell count and in those with FLT3-ITD or MLL rearrangement. When combining these 2 molecular abnormalities for comparison of the effect of GM-CSF priming, the difference in terms of EFS was highly significant (5-year EFS, 39% with GM-CSF vs 8% without GM-CSF; P = .007). : Sensitization of leukemic cells and their progenitors by GM-CSF appears as a plausible strategy for improving the outcome of patients with newly diagnosed AML. Patients with poor-prognosis FLT3-ITD or MLL rearrangement might be a good target population to further investigate priming strategies. Cancer 2010. (c) 2010 American Cancer Society.

Laboratory Investigation of Expansion and Venting and Plug Response in the MX Trench.

DTIC Science & Technology

1979-02-01

twnch is it hotoi. [’i’-t lb) W~ls t’olld(itd I-r il no0111a I 1rLt I I ,C tLit prl( SIrt OL’f 2 1 1 )S pi. SOil Irf1oil thi IL\\V 1 11051 F5S1 to Ua W...hloc ks bn,;ian to opc -n 111) . SCVCla Il add i tL/Io;il I .r [1ks Ircl :11 OSt immc!Ld 1;ltc lV. (The", (’[ll 1wscl cilsil :Vit t - i IhLc roof I

Evaluation of an Impedance Threshold Device as a VIIP Countermeasure

NASA Technical Reports Server (NTRS)

Ebert, Douglas; Macias, Brandon; Sargsyan, Ashot; Garcia, Kathleen; Stenger, Michael; Hargens, Alan; Johnston, Smith; Kemp, David; Danielson, Richard

2017-01-01

Visual Impairment/Intracranial Pressure (VIIP) is a top human spaceflight risk for which NASA does not currently have a proven mitigation strategy. Thigh cuffs and lower body negative pressure (LBNP) devices have been or are currently being evaluated as a means to reduce VIIP signs and symptoms, but these methods alone may not provide sufficient relief of cephalic venous congestion and VIIP symptoms. Additionally, current LBNP devices are too large and cumbersome for their systematic use as a countermeasure. Therefore, a novel approach is needed that is easy to implement and provides specific relief of symptoms. This investigation will evaluate an impedance threshold device (ITD) as a VIIP countermeasure.

A real-time biomimetic acoustic localizing system using time-shared architecture

NASA Astrophysics Data System (ADS)

Nourzad Karl, Marianne; Karl, Christian; Hubbard, Allyn

2008-04-01

In this paper a real-time sound source localizing system is proposed, which is based on previously developed mammalian auditory models. Traditionally, following the models, which use interaural time delay (ITD) estimates, the amount of parallel computations needed by a system to achieve real-time sound source localization is a limiting factor and a design challenge for hardware implementations. Therefore a new approach using a time-shared architecture implementation is introduced. The proposed architecture is a purely sample-base-driven digital system, and it follows closely the continuous-time approach described in the models. Rather than having dedicated hardware on a per frequency channel basis, a specialized core channel, shared for all frequency bands is used. Having an optimized execution time, which is much less than the system's sample rate, the proposed time-shared solution allows the same number of virtual channels to be processed as the dedicated channels in the traditional approach. Hence, the time-shared approach achieves a highly economical and flexible implementation using minimal silicon area. These aspects are particularly important in efficient hardware implementation of a real time biomimetic sound source localization system.

Continuation of a Levonorgestrel Intrauterine Device During Hematopoietic Stem Cell Transplant: A Case Report.

PubMed

Brady, Paula C; Soiffer, Robert J; Ginsburg, Elizabeth S

2017-04-01

During treatment of hematologic malignancies in premenopausal women, both menstrual suppression and contraception are crucial. Continuation of hormonal intrauterine devices (IUDs) - widely used and highly effective contraceptives that also decrease menstrual flow - is controversial during hematopoietic stem cell transplants (SCTs) due to infectious and vaginal bleeding concerns. A 23-year-old nulligravid female was diagnosed with acute myeloid leukemia (AML, positive for FLT3-ITD, DNMT3A and RUNX1, with normal cytogenetics). She elected to retain her existing levonorgestrel-containing IUD during chemotherapy and SCT. During and following treatment, she remained amenorrheic without infection, despite severe neutropenia and thrombocytopenia. Eight months later, she remains in remission without IUD-related complications. This is the first report of levonorgestrel IUD retention during hematopoietic SCT. Despite severe neutropenia and thrombocytopenia, the patient developed neither pelvic infection by retaining her IUD nor significant vaginal bleeding. Future studies are needed to confirm the safety of levonorgestrel IUDs in women undergoing SCT. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Evaluation of an Impedance Threshold Device as a VIIP Countermeasure

NASA Technical Reports Server (NTRS)

Ebert, D.; Macias, B.; Sargsyan, A.; Garcia, K.; Stenger, M.; Kemp, D.; Hargens, A.; Johnston, S.

2017-01-01

Visual Impairment/Intracranial Pressure (VIIP) is a top human spaceflight risk for which NASA does not currently have a proven mitigation strategy. Thigh cuffs (Braslets) and lower body negative pressure (LBNP; Chibis) devices have been or are currently being evaluated as a means to reduce VIIP signs and symptoms, but these methods alone may not provide sufficient relief of cephalic venous congestion and VIIP symptoms. Additionally, current LBNP devices are too large and cumbersome for their systematic use as a countermeasure. Therefore, a novel approach is needed that is easy to implement and provides specific relief of symptoms. This investigation will evaluate an impedance threshold device (ITD) as a VIIP countermeasure.

Congenital dyshormonogenic hypothyroidism with goiter caused by a sodium/iodide symporter (SLC5A5) mutation in a family of Shih-Tzu dogs.

PubMed

Soler Arias, E A; Castillo, V A; Garcia, J D; Fyfe, J C

2018-04-24

An iodide transport defect (ITD) in the thyroid gland was determined to cause congenital dyshormonogenic hypothyroidism with goiter (CDHG) in 2 members of a family of Shih-Tzu dogs. Strikingly, both dogs were also diagnosed with dilated cardiomyopathy at 24 and 1.5 mo of age. The only sign of hypothyroidism was a moderate growth delay in the adult dog. The ITD was recognized by the absence of uptake of technetium-99m in the salivary glands (sg) and goiter observed by scintigraphy. In the same scan, radiopharmaceutical uptake was found in the anterior mediastinum of both dogs and in the right axillary lymph node in the oldest dog. A follicular thyroid carcinoma was diagnosed by histopathology after thyroidectomy of the older dog. An adenomatous goiter with ectopic thyroid tissue, and degenerative changes in myocardium were the findings after necropsy in the youngest dog. A homozygous mutation of the intron 9 splice acceptor site of SLC5A5 gene, encoding the sodium/iodine symporter (NIS), was found in the DNA of one of the affected dogs. The mutation was a single base transition of guanine > adenine (G > A) at position 45,024,672 of dog chromosome 20 (CFA20). Five of eight healthy dogs, including both parents of one of the dogs exhibiting CDHG, were heterozygous A/G, and the other 3 were homozygous for the wild-type allele G/G. No sequence variant was found in thyroid peroxidase of the affected dog. Congenital dyshormonogenic hypothyroidism with goiter in this family is an autosomal recessive trait. Our findings are the first evidence of an SLC5A5 mutation in dogs and establish a new genetic cause of CDHG. Copyright © 2018 Elsevier Inc. All rights reserved.

The Effect of Head Up Cardiopulmonary Resuscitation on Cerebral and Systemic Hemodynamics.

PubMed

Ryu, Hyun Ho; Moore, Johanna C; Yannopoulos, Demetris; Lick, Michael; McKnite, Scott; Shin, Sang Do; Kim, Tae Yun; Metzger, Anja; Rees, Jennifer; Tsangaris, Adamantios; Debaty, Guillaume; Lurie, Keith G

2016-05-01

Chest compressions during cardiopulmonary resuscitation (CPR) increase arterial and venous pressures, delivering simultaneous bidirectional high-pressure compression waves to the brain. We hypothesized that this may be detrimental and could be partially overcome by elevation of the head during CPR. Female Yorkshire farm pigs (n=30) were sedated, intubated, anesthetized, and placed on a table able to elevate the head 30° (15cm) (HUP) and the heart 10° (4cm) or remain in the supine (SUP) flat position during CPR. After 8minutes of untreated ventricular fibrillation and 2minutes of SUP CPR, pigs were randomized to HUP or SUP CPR for 20 more minutes. In Group A, pigs were randomized after 2minutes of flat automated conventional (C) CPR to HUP (n=7) or SUP (n=7) C-CPR. In Group B, pigs were randomized after 2minutes of automated active compression decompression (ACD) CPR plus an impedance threshold device (ITD) SUP CPR to either HUP (n=8) or SUP (n=8). The primary outcome of the study was difference in CerPP (mmHg) between the HUP and SUP positions within groups. After 22minutes of CPR, CerPP was 6±3mmHg in the HUP versus -5±3 in the SUP (p=0.016) in Group A, and 51±8 versus 20±5 (p=0.006) in Group B. Coronary perfusion pressures after 22minutes were HUP 6±2 vs SUP 3±2 (p=0.283) in Group A and HUP 32±5 vs SUP 19±5, (p=0.074) in Group B. In Group B, 6/8 pigs were resuscitated in both positions. No pigs were resuscitated in Group A. The HUP position in both C-CPR and ACD+ITD CPR significantly improved CerPP. This simple maneuver has the potential to improve neurological outcomes after cardiac arrest. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Interplay between low threshold voltage-gated K+ channels and synaptic inhibition in neurons of the chicken nucleus laminaris along its frequency axis

PubMed Central

Hamlet, William R.; Liu, Yu-Wei; Tang, Zheng-Quan; Lu, Yong

2014-01-01

Central auditory neurons that localize sound in horizontal space have specialized intrinsic and synaptic cellular mechanisms to tightly control the threshold and timing for action potential generation. However, the critical interplay between intrinsic voltage-gated conductances and extrinsic synaptic conductances in determining neuronal output are not well understood. In chicken, neurons in the nucleus laminaris (NL) encode sound location using interaural time difference (ITD) as a cue. Along the tonotopic axis of NL, there exist robust differences among low, middle, and high frequency (LF, MF, and HF, respectively) neurons in a variety of neuronal properties such as low threshold voltage-gated K+ (LTK) channels and depolarizing inhibition. This establishes NL as an ideal model to examine the interactions between LTK currents and synaptic inhibition across the tonotopic axis. Using whole-cell patch clamp recordings prepared from chicken embryos (E17–E18), we found that LTK currents were larger in MF and HF neurons than in LF neurons. Kinetic analysis revealed that LTK currents in MF neurons activated at lower voltages than in LF and HF neurons, whereas the inactivation of the currents was similar across the tonotopic axis. Surprisingly, blockade of LTK currents using dendrotoxin-I (DTX) tended to broaden the duration and increase the amplitude of the depolarizing inhibitory postsynaptic potentials (IPSPs) in NL neurons without dependence on coding frequency regions. Analyses of the effects of DTX on inhibitory postsynaptic currents led us to interpret this unexpected observation as a result of primarily postsynaptic effects of LTK currents on MF and HF neurons, and combined presynaptic and postsynaptic effects in LF neurons. Furthermore, DTX transferred subthreshold IPSPs to spikes. Taken together, the results suggest a critical role for LTK currents in regulating inhibitory synaptic strength in ITD-coding neurons at various frequencies. PMID:24904297

Feasibility of the AML profiler (Skyline™ Array) for patient risk stratification in a multicentre trial: a preliminary comparison with the conventional approach.

PubMed

Nomdedéu, Josep F; Puigdecanet, Eulalia; Bussaglia, Elena; Hernández, Juan José; Carricondo, Maite; Estivill, Camino; Martí-Tutusaus, Josep Maria; Tormo, Mar; Zamora, Lurdes; Serrano, Elena; Perea, Granada; de Llano, Maria Paz Queipo; García, Antoni; Sánchez-Ortega, Isabel; Ribera, Josep Maria; Nonell, Lara; Aventin, Anna; Solé, Francesc; Brunet, Maria Salut; Sierra, Jorge

2017-12-01

Deoxyribonucleic acid microarrays allow researchers to measure mRNA levels of thousands of genes in a single experiment and could be useful for diagnostic purposes in patients with acute myeloid leukaemia (AML). We assessed the feasibility of the AML profiler (Skyline™ Array) in genetic stratification of patients with de novo AML and compared the results with those obtained using the standard cytogenetic and molecular approach. Diagnostic bone marrow from 31 consecutive de novo AML cases was used to test MLL-PTD, FLT3-ITD and TKD, NPM1 and CEBPAdm mutations. Purified RNA was used to assess RUNX1-RUNX1T1, PML-RARα and CBFβ-MYH11 rearrangements. RNA remnants underwent gene expression profiling analysis using the AML profiler, which detects chromosomal aberrations: t(8;21), t(15;17), inv(16), mutations (CEBPAdm, ABD-NPM1) and BAALC and EVI1 expression. Thirty cases were successfully analysed with both methods. Five cases had FLT3-ITD. In one case, a t(8;21) was correctly detected by both methods. Four cases had inv(16); in one, the RNA quality was unsatisfactory and it was not hybridized, and in the other three, the AML profiler detected the genetic lesion - this being a rare type I translocation in one case. Two cases with acute promyelocytic leukaemia were diagnosed by both methods. Results for NPM1 mutations were concordant in all but two cases (2/11, non-ABD mutations). Analysis of costs and turnaround times showed that the AML profiler was no more expensive than the conventional molecular approach. These results suggest that the AML profiler could be useful in multicentre trials to rapidly identify patients with AML with a good prognosis. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Horizontal sound localization in cochlear implant users with a contralateral hearing aid.

PubMed

Veugen, Lidwien C E; Hendrikse, Maartje M E; van Wanrooij, Marc M; Agterberg, Martijn J H; Chalupper, Josef; Mens, Lucas H M; Snik, Ad F M; John van Opstal, A

2016-06-01

Interaural differences in sound arrival time (ITD) and in level (ILD) enable us to localize sounds in the horizontal plane, and can support source segregation and speech understanding in noisy environments. It is uncertain whether these cues are also available to hearing-impaired listeners who are bimodally fitted, i.e. with a cochlear implant (CI) and a contralateral hearing aid (HA). Here, we assessed sound localization behavior of fourteen bimodal listeners, all using the same Phonak HA and an Advanced Bionics CI processor, matched with respect to loudness growth. We aimed to determine the availability and contribution of binaural (ILDs, temporal fine structure and envelope ITDs) and monaural (loudness, spectral) cues to horizontal sound localization in bimodal listeners, by systematically varying the frequency band, level and envelope of the stimuli. The sound bandwidth had a strong effect on the localization bias of bimodal listeners, although localization performance was typically poor for all conditions. Responses could be systematically changed by adjusting the frequency range of the stimulus, or by simply switching the HA and CI on and off. Localization responses were largely biased to one side, typically the CI side for broadband and high-pass filtered sounds, and occasionally to the HA side for low-pass filtered sounds. HA-aided thresholds better than 45 dB HL in the frequency range of the stimulus appeared to be a prerequisite, but not a guarantee, for the ability to indicate sound source direction. We argue that bimodal sound localization is likely based on ILD cues, even at frequencies below 1500 Hz for which the natural ILDs are small. These cues are typically perturbed in bimodal listeners, leading to a biased localization percept of sounds. The high accuracy of some listeners could result from a combination of sufficient spectral overlap and loudness balance in bimodal hearing. Copyright © 2016 Elsevier B.V. All rights reserved.

Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group.

PubMed

Boissel, Nicolas; Nibourel, Olivier; Renneville, Aline; Gardin, Claude; Reman, Oumedaly; Contentin, Nathalie; Bordessoule, Dominique; Pautas, Cécile; de Revel, Thierry; Quesnel, Bruno; Huchette, Pascal; Philippe, Nathalie; Geffroy, Sandrine; Terre, Christine; Thomas, Xavier; Castaigne, Sylvie; Dombret, Hervé; Preudhomme, Claude

2010-08-10

Recently, whole-genome sequencing in acute myeloid leukemia (AML) identified recurrent isocitrate dehydrogenase enzyme isoform (IDH1) mutations (IDH1m), previously reported to be involved in gliomas as well as IDH2 mutations (IDH2m). The prognosis of both IDH1m and IDH2m in AML remains unclear. The prevalence and the prognostic impact of R132 IDH1 and R172 IDH2 mutations were evaluated in a cohort of 520 adults with AML homogeneously treated in the French Acute Leukemia French Association (ALFA) -9801 and -9802 trials. The prevalence of IDH1m and IDH2m was 9.6% and 3.0%, respectively, mostly associated with normal cytogenetics (CN). In patients with CN-AML, IDH1m were associated with NPM1m (P = .008), but exclusive of CEBPAm (P = .03). In contrary, no other mutations were detected in IDH2m patients. In CN-AML patients, IDH1m were found in 19% of favorable genotype ([NPM1m or CEBPAm] without fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ITD]) and were associated with a higher risk of relapse (RR) and a shorter overall survival (OS). Favorable genotype in CN-AML could thus be defined by the association of NPM1m or CEBPAm with neither FLT3-ITD nor IDH1m. In IDH2m CN-AML patients, we observed a higher risk of induction failure, a higher RR and a shorter OS. In multivariate analysis, age, WBC count, the four-gene favorable genotype and IDH2m were independently associated with a higher RR and a shorter OS. Contrarily to what is reported in gliomas, IDH1m and IDH2m in AML are associated with a poor prognosis. Screening of IDH1m could help to identify high-risk patients within the subset of CN-AML with a favorable genotype.

Physiological models of the lateral superior olive

PubMed Central

2017-01-01

In computational biology, modeling is a fundamental tool for formulating, analyzing and predicting complex phenomena. Most neuron models, however, are designed to reproduce certain small sets of empirical data. Hence their outcome is usually not compatible or comparable with other models or datasets, making it unclear how widely applicable such models are. In this study, we investigate these aspects of modeling, namely credibility and generalizability, with a specific focus on auditory neurons involved in the localization of sound sources. The primary cues for binaural sound localization are comprised of interaural time and level differences (ITD/ILD), which are the timing and intensity differences of the sound waves arriving at the two ears. The lateral superior olive (LSO) in the auditory brainstem is one of the locations where such acoustic information is first computed. An LSO neuron receives temporally structured excitatory and inhibitory synaptic inputs that are driven by ipsi- and contralateral sound stimuli, respectively, and changes its spike rate according to binaural acoustic differences. Here we examine seven contemporary models of LSO neurons with different levels of biophysical complexity, from predominantly functional ones (‘shot-noise’ models) to those with more detailed physiological components (variations of integrate-and-fire and Hodgkin-Huxley-type). These models, calibrated to reproduce known monaural and binaural characteristics of LSO, generate largely similar results to each other in simulating ITD and ILD coding. Our comparisons of physiological detail, computational efficiency, predictive performances, and further expandability of the models demonstrate (1) that the simplistic, functional LSO models are suitable for applications where low computational costs and mathematical transparency are needed, (2) that more complex models with detailed membrane potential dynamics are necessary for simulation studies where sub-neuronal nonlinear processes play important roles, and (3) that, for general purposes, intermediate models might be a reasonable compromise between simplicity and biological plausibility. PMID:29281618

Interplay between low threshold voltage-gated K(+) channels and synaptic inhibition in neurons of the chicken nucleus laminaris along its frequency axis.

PubMed

Hamlet, William R; Liu, Yu-Wei; Tang, Zheng-Quan; Lu, Yong

2014-01-01

Central auditory neurons that localize sound in horizontal space have specialized intrinsic and synaptic cellular mechanisms to tightly control the threshold and timing for action potential generation. However, the critical interplay between intrinsic voltage-gated conductances and extrinsic synaptic conductances in determining neuronal output are not well understood. In chicken, neurons in the nucleus laminaris (NL) encode sound location using interaural time difference (ITD) as a cue. Along the tonotopic axis of NL, there exist robust differences among low, middle, and high frequency (LF, MF, and HF, respectively) neurons in a variety of neuronal properties such as low threshold voltage-gated K(+) (LTK) channels and depolarizing inhibition. This establishes NL as an ideal model to examine the interactions between LTK currents and synaptic inhibition across the tonotopic axis. Using whole-cell patch clamp recordings prepared from chicken embryos (E17-E18), we found that LTK currents were larger in MF and HF neurons than in LF neurons. Kinetic analysis revealed that LTK currents in MF neurons activated at lower voltages than in LF and HF neurons, whereas the inactivation of the currents was similar across the tonotopic axis. Surprisingly, blockade of LTK currents using dendrotoxin-I (DTX) tended to broaden the duration and increase the amplitude of the depolarizing inhibitory postsynaptic potentials (IPSPs) in NL neurons without dependence on coding frequency regions. Analyses of the effects of DTX on inhibitory postsynaptic currents led us to interpret this unexpected observation as a result of primarily postsynaptic effects of LTK currents on MF and HF neurons, and combined presynaptic and postsynaptic effects in LF neurons. Furthermore, DTX transferred subthreshold IPSPs to spikes. Taken together, the results suggest a critical role for LTK currents in regulating inhibitory synaptic strength in ITD-coding neurons at various frequencies.

Experimental validation of a true-scale morphing flap for large civil aircraft applications

NASA Astrophysics Data System (ADS)

Pecora, R.; Amoroso, F.; Arena, M.; Noviello, M. C.; Rea, F.

2017-04-01

Within the framework of the JTI-Clean Sky (CS) project, and during the first phase of the Low Noise Configuration Domain of the Green Regional Aircraft - Integrated Technological Demonstration (GRA-ITD, the preliminary design and technological demonstration of a novel wing flap architecture were addressed. Research activities were carried out to substantiate the feasibility of morphing concepts enabling flap camber variation in compliance with the demanding safety requirements applicable to the next generation green regional aircraft, 130- seats with open rotor configuration. The driving motivation for the investigation on such a technology was found in the opportunity to replace a conventional double slotted flap with a single slotted camber-morphing flap assuring similar high lift performances -in terms of maximum attainable lift coefficient and stall angle- while lowering emitted noise and system complexity. Studies and tests were limited to a portion of the flap element obtained by slicing the actual flap geometry with two cutting planes distant 0.8 meters along the wing span. Further activities were then addressed in order to increase the TRL of the validated architecture within the second phase of the CS-GRA. Relying upon the already assessed concept, an innovative and more advanced flap device was designed in order to enable two different morphing modes on the basis of the A/C flight condition / flap setting: Mode1, Overall camber morphing to enhance high-lift performances during take-off and landing (flap deployed); Mode2, Tab-like morphing mode. Upwards and downwards deflection of the flap tip during cruise (flap stowed) for load control at high speed. A true-scale segment of the outer wing flap (4 meters span with a mean chord of 0.9 meters) was selected as investigation domain for the new architecture in order to duly face the challenges posed by real wing installation. Advanced and innovative solutions for the adaptive structure, actuation and control systems were duly analyzed and experimentally validated thus proving the overall device compliance with industrial standards and applicable airworthiness requirements.

The binaural performance of a cross-talk cancellation system with matched or mismatched setup and playback acoustics

PubMed Central

Akeroyd, Michael A.; Chambers, John; Bullock, David; Palmer, Alan R.; Summerfield, A. Quentin; Nelson, Philip A.; Gatehouse, Stuart

2013-01-01

Cross-talk cancellation is a method for synthesising virtual auditory space using loudspeakers. One implementation is the “Optimal Source Distribution” technique [T. Takeuchi and P. Nelson, J. Acoust. Soc. Am. 112, 2786-2797 (2002)], in which the audio bandwidth is split across three pairs of loudspeakers, placed at azimuths of ±90°, ±15°, and ±3°, conveying low, mid and high frequencies, respectively. A computational simulation of this system was developed and verified against measurements made on an acoustic system using a manikin. Both the acoustic system and the simulation gave a wideband average cancellation of almost 25 dB. The simulation showed that when there was a mismatch between the head-related transfer functions used to set up the system and those of the final listener, the cancellation was reduced to an average of 13 dB. Moreover, in this case the binaural ITDs and ILDs delivered by the simulation of the OSD system often differed from the target values. It is concluded that only when the OSD system is set up with “matched” head-related transfer functions can it deliver accurate binaural cues. PMID:17348528

Clinical and pathological features of myeloid leukemia cutis*

PubMed Central

Li, Li; Wang, Yanan; Lian, Christine Guo; Hu, Nina; Jin, Hongzhong; Liu, Yuehua

2018-01-01

Background Myeloid leukemia cutis is the terminology used for cutaneous manifestations of myeloid leukemia. Objective The purpose of this study was to study the clinical, histopathological and immunohistochemical features of myeloid leukemia cutis. Methods This was a retrospective study of clinical and pathological features of 10 patients with myeloid leukemia cutis. Results One patient developed skin lesions before the onset of leukemia, seven patients developed skin infiltration within 4-72 months after the onset of leukemia, and two patients developed skin lesions and systemic leukemia simultaneously. Of these patients, five presented with generalized papules or nodules, and five with localized masses. The biopsy of skin lesions showed a large number of tumor cells within the dermis and subcutaneous fat layer. Immunohistochemical analysis showed strong reactivity to myeloperoxidase (MPO), CD15, CD43 and CD45 (LCA) in most cases. NPM1 (nucleophosmin I) and FLT3-ITD (Fms-like tyrosine kinase 3-internal tandem duplication) mutations were identified in one case. Five patients with acute myelogenous leukemia and one patient with chronic myelomonocytic leukemia died within two months to one year after the onset of skin lesions. Study limitations This was a retrospective and small sample study. Conclusions In patients with myelogenous leukemia, skin infiltration usually occurs after, but occasionally before, the appearance of hemogram and myelogram abnormalities, and the presence of skin infiltration is often associated with a poor prognosis and short survival time. myeloid leukemia cutis often presents as generalized or localized nodules or masses with characteristic pathological and histochemical findings. PMID:29723350

A Counterexample Concerning the External index

DTIC Science & Technology

1988-08-01

et al. For a suitable sequence (rn) satisfying rn 4 w, rn/n 4 O , let rn r n Tn(j) -P( E Xni j i Xni > 0), j-1,2.... (5) i-i i1l where Xn,i is 1 if...Appromd for pubW 7~~ o . Dittrbutiona tln~mItd 10 9 N I. 20 1tIC 1 0 - a pi 00 I 11 3 0 06 -6 .. 02~ ’ x. a C-L d e a A 0i 0 - Ss 0 - 8 go ip9 d vi . -C...PERSONAL AUTHO..S) Smith, R.L. 13. TYPE OF REPORT 13b. TIME COVERED 14. DATE OF REPORT (Yr...WE.. Day) 15. PAGE COUNT r rint FROM 91/87_ TO 8L31/8

Hypoxia-Activated Prodrug TH-302 Targets Hypoxic Bone Marrow Niches in Preclinical Leukemia Models.

PubMed

Benito, Juliana; Ramirez, Marc S; Millward, Niki Zacharias; Velez, Juliana; Harutyunyan, Karine G; Lu, Hongbo; Shi, Yue-Xi; Matre, Polina; Jacamo, Rodrigo; Ma, Helen; Konoplev, Sergej; McQueen, Teresa; Volgin, Andrei; Protopopova, Marina; Mu, Hong; Lee, Jaehyuk; Bhattacharya, Pratip K; Marszalek, Joseph R; Davis, R Eric; Bankson, James A; Cortes, Jorge E; Hart, Charles P; Andreeff, Michael; Konopleva, Marina

2016-04-01

To characterize the prevalence of hypoxia in the leukemic bone marrow, its association with metabolic and transcriptional changes in the leukemic blasts and the utility of hypoxia-activated prodrug TH-302 in leukemia models. Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate the pyruvate metabolism of the bone marrow in the murine acute myeloid leukemia (AML) model. Nanostring technology was used to evaluate a gene set defining a hypoxia signature in leukemic blasts and normal donors. The efficacy of the hypoxia-activated prodrug TH-302 was examined in the in vitro and in vivo leukemia models. Metabolic imaging has demonstrated increased glycolysis in the femur of leukemic mice compared with healthy control mice, suggesting metabolic reprogramming of hypoxic bone marrow niches. Primary leukemic blasts in samples from AML patients overexpressed genes defining a "hypoxia index" compared with samples from normal donors. TH-302 depleted hypoxic cells, prolonged survival of xenograft leukemia models, and reduced the leukemia stem cell pool in vivo In the aggressive FLT3/ITD MOLM-13 model, combination of TH-302 with tyrosine kinase inhibitor sorafenib had greater antileukemia effects than either drug alone. Importantly, residual leukemic bone marrow cells in a syngeneic AML model remain hypoxic after chemotherapy. In turn, administration of TH-302 following chemotherapy treatment to mice with residual disease prolonged survival, suggesting that this approach may be suitable for eliminating chemotherapy-resistant leukemia cells. These findings implicate a pathogenic role of hypoxia in leukemia maintenance and chemoresistance and demonstrate the feasibility of targeting hypoxic cells by hypoxia cytotoxins. ©2015 American Association for Cancer Research.

Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model.

PubMed

Burkholder, Timothy P; Clayton, Joshua R; Rempala, Mark E; Henry, James R; Knobeloch, John M; Mendel, David; McLean, Johnathan A; Hao, Yan; Barda, David A; Considine, Eileen L; Uhlik, Mark T; Chen, Yuefeng; Ma, Liandong; Bloem, Laura J; Akunda, Jacqueline K; McCann, Denis J; Sanchez-Felix, Manuel; Clawson, David K; Lahn, Michael M; Starling, James J

2012-06-01

LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of receptors. With activities against both Tie2 and Eph receptors, LY2457546 possesses an activity profile that distinguishes it from multikinase inhibitors. When compared head to head with sunitinib, LY2457546 was more potent for inhibition of endothelial tube formation in an in vitro angiogenesis co-culture model with an intermittent treatment design. In vivo, LY2457546 inhibited VEGF-driven autophosphorylation of lung KDR in the mouse and rat in a dose and concentration dependent manner. LY2457546 was well tolerated and exhibited efficacy in a 13762 syngeneic rat mammary tumor model in both once and twice daily continuous dosing schedules and in mouse human tumor xenograft models of lung, colon, and prostate origin. Additionally, LY2457546 caused complete regression of well-established tumors in an acute myelogenous leukemia (AML) FLT3-ITD mutant xenograft tumor model. The observed efficacy that was displayed by LY2457546 in the AML FLT3-ITD mutant tumor model was superior to sunitinib when both were evaluated using equivalent doses normalized to in vivo inhibition of pKDR in mouse lung. LY2457546 was well tolerated in non-clinical toxicology studies conducted in rats and dogs. The majority of the toxicities observed were similar to those observed with other multi-targeted anti-angiogenic kinase inhibitors (MAKs) and included bone marrow hypocellularity, hair and skin depigmentation, cartilage dysplasia and lymphoid organ degeneration and necrosis. Thus, the unique spectrum of target activity, potent in vivo anti-tumor efficacy in a variety of rodent and human solid tumor models, exquisite potency against a clinically relevant model of AML, and non-clinical safety profile justify the advancement of LY2457546 into clinical testing.

DNMT3A mutations in Chinese childhood acute myeloid leukemia.

PubMed

Li, Weijing; Cui, Lei; Gao, Chao; Liu, Shuguang; Zhao, Xiaoxi; Zhang, Ruidong; Zheng, Huyong; Wu, Minyuan; Li, Zhigang

2017-08-01

DNA methyltransferase 3A (DNMT3A) mutations have been found in approximately 20% of adult acute myeloid leukemia (AML) patients and in 0% to 1.4% of children with AML, and the hotspots of mutations are mainly located in the catalytic methyltransferase domain, hereinto, mutation R882 accounts for 60%. Although the negative effect of DNMT3A on treatment outcome is well known, the prognostic significance of other DNMT3A mutations in AML is still unclear. Here, we tried to determine the incidence and prognostic significance of DNMT3A mutations in a large cohort in Chinese childhood AML. We detected the mutations in DNMT3A exon 23 by polymerase chain reaction and direct sequencing in 342 children with AML (0-16 years old) from January 2005 to June 2013, treated on BCH-2003 AML protocol. The correlation of DNMT3A mutations with clinical characteristics, fusion genes, other molecular anomalies (FLT3 internal tandem duplication [FLT3-ITD], Nucleophosmin 1, C-KIT (KIT proto-oncogene receptor tyrosine kinase), and Wilms tumor 1 mutations), and treatment outcome were analyzed. DNMT3A mutations were detected in 4 out of 342 (1.2%) patients. Two patients were PML-RARA positive and 1 patient was FLT3-ITD positive. The mutations in coding sequences included S892S, V912A, R885G, and Q886R. Furthermore, there was 1 intronic mutation (c.2739+55A>C) found in 1 patient. No association of DNMT3A mutations with common clinical features was found. Two patients with DNMT3A mutations died of relapse or complications during treatment. One patient gave up treatment due to remission induction failure in day 33. Only 1 patient achieved continuous complete remission. DNMT3A mutations were rare in Chinese children with AML including PML-RARA positive APL. The mutation positions were different from the hotspots reported in adult AML. DNMT3A mutations may have adverse impact on prognosis of children with AML.

Transformation by oncogenic mutants and ligand-dependent activation of FLT3 wild-type requires the tyrosine residues 589 and 591.

PubMed

Vempati, Sridhar; Reindl, Carola; Wolf, Ulla; Kern, Ruth; Petropoulos, Konstantin; Naidu, Vegi M; Buske, Christian; Hiddemann, Wolfgang; Kohl, Tobias M; Spiekermann, Karsten

2008-07-15

Mutations in the receptor tyrosine kinase FLT3 are found in up to 30% of acute myelogenous leukemia patients and are associated with an inferior prognosis. In this study, we characterized critical tyrosine residues responsible for the transforming potential of active FLT3-receptor mutants and ligand-dependent activation of FLT3-WT. We performed a detailed structure-function analysis of putative autophosphorylation tyrosine residues in the FLT3-D835Y tyrosine kinase domain (TKD) mutant. All tyrosine residues in the juxtamembrane domain (Y566, Y572, Y589, Y591, Y597, and Y599), interkinase domain (Y726 and Y768), and COOH-terminal domain (Y955 and Y969) of the FLT3-D835Y construct were successively mutated to phenylalanine and the transforming activity of these mutants was analyzed in interleukin-3-dependent Ba/F3 cells. Tyrosine residues critical for the transforming potential of FLT3-D835Y were also analyzed in FLT3 internal tandem duplication mutants (FLT3-ITD)and the FLT3 wild-type (FLT3-WT) receptor. The substitution of the tyrosine residues by phenylalanine in the juxtamembrane, interkinase, and COOH-terminal domains resulted in a complete loss of the transforming potential of FLT3-D835Y-expressing cells which can be attributed to a significant reduction of signal tranducer and activator of transcription 5 (STAT5) phosphorylation at the molecular level. Reintroduction of single tyrosine residues revealed the critical role of Y589 and Y591 in reconstituting interleukin-3-independent growth of FLT3-TKD-expressing cells. Combined mutation of Y589 and Y591 to phenylalanine also abrogated ligand-dependent proliferation of FLT3-WT and the transforming potential of FLT3-ITD-with a subsequent abrogation of STAT5 phosphorylation. We identified two tyrosine residues, Y589 and Y591, in the juxtamembrane domain that are critical for the ligand-dependent activation of FLT3-WT and the transforming potential of oncogenic FLT3 mutants.

Electrodialytic matrix isolation for metal cations.

PubMed

Ohira, Shin-Ichi; Hiroyama, Yuri; Nakamura, Koretaka; Koda, Takumi; Dasgupta, Purnendu K; Toda, Kei

2015-01-01

Electrodialytic ion transfer was studied as a matrix isolation tool for heavy metal determinations. An ion transfer device (ITD) was used for the transfer of heavy metal cations. Under optimized flow rates applied voltage and receptor composition, heavy metal ions were quantitatively transferred at concentrations spanning µg L(-1) to mg L(-1). As long as the sample pH was acidic, there was no significant sample pH effect on the transfer efficiencies. Significant salt concentrations (>1 mM NaCl), however, decreased the transfer efficiency. This could be ameliorated (up to 5 mM NaCl) by transient instead of continuous sample introduction. The device was applied to the determination of Fe, Cu and Zn in equine and bovine serum; the reproducibility was better than conventional digestion method. Copyright © 2014 Elsevier B.V. All rights reserved.

Neuromorphic audio-visual sensor fusion on a sound-localizing robot.

PubMed

Chan, Vincent Yue-Sek; Jin, Craig T; van Schaik, André

2012-01-01

This paper presents the first robotic system featuring audio-visual (AV) sensor fusion with neuromorphic sensors. We combine a pair of silicon cochleae and a silicon retina on a robotic platform to allow the robot to learn sound localization through self motion and visual feedback, using an adaptive ITD-based sound localization algorithm. After training, the robot can localize sound sources (white or pink noise) in a reverberant environment with an RMS error of 4-5° in azimuth. We also investigate the AV source binding problem and an experiment is conducted to test the effectiveness of matching an audio event with a corresponding visual event based on their onset time. Despite the simplicity of this method and a large number of false visual events in the background, a correct match can be made 75% of the time during the experiment.

a Unified Matrix Polynomial Approach to Modal Identification

NASA Astrophysics Data System (ADS)

Allemang, R. J.; Brown, D. L.

1998-04-01

One important current focus of modal identification is a reformulation of modal parameter estimation algorithms into a single, consistent mathematical formulation with a corresponding set of definitions and unifying concepts. Particularly, a matrix polynomial approach is used to unify the presentation with respect to current algorithms such as the least-squares complex exponential (LSCE), the polyreference time domain (PTD), Ibrahim time domain (ITD), eigensystem realization algorithm (ERA), rational fraction polynomial (RFP), polyreference frequency domain (PFD) and the complex mode indication function (CMIF) methods. Using this unified matrix polynomial approach (UMPA) allows a discussion of the similarities and differences of the commonly used methods. the use of least squares (LS), total least squares (TLS), double least squares (DLS) and singular value decomposition (SVD) methods is discussed in order to take advantage of redundant measurement data. Eigenvalue and SVD transformation methods are utilized to reduce the effective size of the resulting eigenvalue-eigenvector problem as well.

Coupled LC-GC techniques for the characterisation of polycyclic aromatic compounds in fuel materials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Askey, S.A.; Holden, K.M.L.; Bartle, K.D.

1995-12-31

Exposure to polycyclic aromatic compounds (PAC) has long been identified as of considerable environmental concern. Originating from both natural and anthropogenic sources, many PAC exhibit significant carcinogenic and mutagenic properties. Multi-dimensional chromatographic techniques which provide separation by virtue of chemical class (group-type) or by molecular mass greatly simplifies the analysis of inherently complex fuel materials. In this study, on-line LC-GC techniques in which high resolution gas chromatography (HPLC) have been investigated. Comprehensive characterisation of fuel feedstocks and post-pyrolysis and combustion products was achieved by coupling LC-GC to low resolution ion trap mass spectrometry (ITD-MS) and atomic emission detection (AED). Themore » identification of PAC in diesel and coal materials, as well as urban air and diesel exhaust particulate extracts has provided valuable insight into the source, formation and distribution of such compounds pre- and post processing.« less

Fludarabine Phosphate, Cyclophosphamide, Total Body Irradiation, and Donor Stem Cell Transplant in Treating Patients With Blood Cancer

ClinicalTrials.gov

2018-06-13

Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Acute Leukemia in Remission; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Acute Myeloid Leukemia With FLT3/ITD Mutation; Acute Myeloid Leukemia With Gene Mutations; Aplastic Anemia; B-Cell Non-Hodgkin Lymphoma; CD40 Ligand Deficiency; Chronic Granulomatous Disease; Chronic Leukemia in Remission; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Congenital Amegakaryocytic Thrombocytopenia; Congenital Neutropenia; Congenital Pure Red Cell Aplasia; Glanzmann Thrombasthenia; Immunodeficiency Syndrome; Myelodysplastic Syndrome; Myelofibrosis; Myeloproliferative Neoplasm; Paroxysmal Nocturnal Hemoglobinuria; Plasma Cell Myeloma; Polycythemia Vera; Recurrent Non-Hodgkin Lymphoma; Refractory Non-Hodgkin Lymphoma; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Severe Aplastic Anemia; Shwachman-Diamond Syndrome; Sickle Cell Disease; T-Cell Non-Hodgkin Lymphoma; Thalassemia; Waldenstrom Macroglobulinemia; Wiskott-Aldrich Syndrome

Clinical evaluation of panel testing by next-generation sequencing (NGS) for gene mutations in myeloid neoplasms.

PubMed

Au, Chun Hang; Wa, Anna; Ho, Dona N; Chan, Tsun Leung; Ma, Edmond S K

2016-01-22

Genomic techniques in recent years have allowed the identification of many mutated genes important in the pathogenesis of acute myeloid leukemia (AML). Together with cytogenetic aberrations, these gene mutations are powerful prognostic markers in AML and can be used to guide patient management, for example selection of optimal post-remission therapy. The mutated genes also hold promise as therapeutic targets themselves. We evaluated the applicability of a gene panel for the detection of AML mutations in a diagnostic molecular pathology laboratory. Fifty patient samples comprising 46 AML and 4 other myeloid neoplasms were accrued for the study. They consisted of 19 males and 31 females at a median age of 60 years (range: 18-88 years). A total of 54 genes (full coding exons of 15 genes and exonic hotspots of 39 genes) were targeted by 568 amplicons that ranged from 225 to 275 bp. The combined coverage was 141 kb in sequence length. Amplicon libraries were prepared by TruSight myeloid sequencing panel (Illumina, CA) and paired-end sequencing runs were performed on a MiSeq (Illumina) genome sequencer. Sequences obtained were analyzed by in-house bioinformatics pipeline, namely BWA-MEM, Samtools, GATK, Pindel, Ensembl Variant Effect Predictor and a novel algorithm ITDseek. The mean count of sequencing reads obtained per sample was 3.81 million and the mean sequencing depth was over 3000X. Seventy-seven mutations in 24 genes were detected in 37 of 50 samples (74 %). On average, 2 mutations (range 1-5) were detected per positive sample. TP53 gene mutations were found in 3 out of 4 patients with complex and unfavorable cytogenetics. Comparing NGS results with that of conventional molecular testing showed a concordance rate of 95.5 %. After further resolution and application of a novel bioinformatics algorithm ITDseek to aid the detection of FLT3 internal tandem duplication (ITD), the concordance rate was revised to 98.2 %. Gene panel testing by NGS approach was applicable for sensitive and accurate detection of actionable AML gene mutations in the clinical laboratory to individualize patient management. A novel algorithm ITDseek was presented that improved the detection of FLT3-ITD of varying length, position and at low allelic burden.

Sound-direction identification, interaural time delay discrimination, and speech intelligibility advantages in noise for a bilateral cochlear implant user.

PubMed

Van Hoesel, Richard; Ramsden, Richard; Odriscoll, Martin

2002-04-01

To characterize some of the benefits available from using two cochlear implants compared with just one, sound-direction identification (ID) abilities, sensitivity to interaural time delays (ITDs) and speech intelligibility in noise were measured for a bilateral multi-channel cochlear implant user. Sound-direction ID in the horizontal plane was tested with a bilateral cochlear implant user. The subject was tested both unilaterally and bilaterally using two independent behind-the-ear ESPRIT (Cochlear Ltd.) processors, as well as bilaterally using custom research processors. Pink noise bursts were presented using an 11-loudspeaker array spanning the subject's frontal 180 degrees arc in an anechoic room. After each burst, the subject was asked to identify which loudspeaker had produced the sound. No explicit training, and no feedback were given. Presentation levels were nominally at 70 dB SPL, except for a repeat experiment using the clinical devices where the presentation levels were reduced to 60 dB SPL to avoid activation of the devices' automatic gain control (AGC) circuits. Overall presentation levels were randomly varied by +/- 3 dB. For the research processor, a "low-update-rate" and a "high-update-rate" strategy were tested. Direct measurements of ITD just noticeable differences (JNDs) were made using a 3 AFC paradigm targeting 70% correct performance on the psychometric function. Stimuli included simple, low-rate electrical pulse trains as well as high-rate pulse trains modulated at 100 Hz. Speech data comparing monaural and binaural performance in noise were also collected with both low, and high update-rate strategies on the research processors. Open-set sentences were presented from directly in front of the subject and competing multi-talker babble noise was presented from the same loudspeaker, or from a loudspeaker placed 90 degrees to the left or right of the subject. For the sound-direction ID task, monaural performance using the clinical devices showed large mean absolute errors of 81 degrees and 73 degrees, with standard deviations (averaged across all 11 loud-speakers) of 10 degrees and 17 degrees, for left and right ears, respectively. Fore bilateral device use at a presentation level of 70 dB SPL, the mean error improved to about 16 degrees with an average standard deviation of 18 degrees. When the presentation level was decreased to 60 dB SPL to avoid activation of the automatic gain control (AGC) circuits in the clinical processors, the mean response error improved further to 8 degrees with a standard deviation of 13 degrees. Further tests with the custom research processors, which had a higher stimulation rate and did not include AGCs, showed comparable response errors: around 8 or 9 degrees and a standard deviation of about 11 degrees for both update rates. The best ITD JNDs measured for this subject were between 350 to 400 microsec for simple low-rate pulse trains. Speech results showed a substantial headshadow advantage for bilateral device use when speech and noise were spatially separated, but little evidence of binaural unmasking. For spatially coincident speech and noise, listening with both ears showed similar results to listening with either side alone when loudness summation was compensated for. No significant differences were observed between binaural results for high and low update-rates in any test configuration. Only for monaural listening in one test configuration did the high rate show a small significant improvement over the low rate. Results show that even if interaural time delay cues are not well coded or perceived, bilateral implants can offer important advantages, both for speech in noise as well as for sound-direction identification.

Prognostic nomogram for previously untreated adult patients with acute myeloid leukemia

PubMed Central

Zheng, Zhuojun; Li, Xiaodong; Zhu, Yuandong; Gu, Weiying; Xie, Xiaobao; Jiang, Jingting

2016-01-01

This study was designed to perform an acceptable prognostic nomogram for acute myeloid leukemia. The clinical data from 311 patients from our institution and 165 patients generated with Cancer Genome Atlas Research Network were reviewed. A prognostic nomogram was designed according to the Cox's proportional hazard model to predict overall survival (OS). To compare the capacity of the nomogram with that of the current prognostic system, the concordance index (C-index) was used to validate the accuracy as well as the calibration curve. The nomogram included 6 valuable variables: age, risk stratifications based on cytogenetic abnormalities, status of FLT3-ITD mutation, status of NPM1 mutation, expression of CD34, and expression of HLA-DR. The C-indexes were 0.71 and 0.68 in the primary and validation cohort respectively, which were superior to the predictive capacity of the current prognostic systems in both cohorts. The nomogram allowed both patients with acute myeloid leukemia and physicians to make prediction of OS individually prior to treatment. PMID:27689396

Experimental study on the damping of FAST cabin suspension system

NASA Astrophysics Data System (ADS)

Li, Hui; Sun, Jing-hai; Zhang, Xin-yu; Zhu, Wen-bai; Pan, Gao-feng; Yang, Qing-ge

2012-09-01

The focus cabin suspension of the FAST telescope has structurally weak-stiffness dynamics with low damping performance, which makes it quite sensitive to wind-induced vibrations. A reasonable estimation about the damping is very important for the control performance evaluation of the prototype. It is a quite difficult task as the telescope is no at available yet. In the paper, a preliminary analysis is first made on the aerodynamic damping. Then a series of experimental models are tested for measuring the total damping. The scales of these models range from 10m to 50m in diameter while 6 test parameters are specially designed to check the damping sensitivity. The Ibrahim time domain (ITD) method is employed to identify the damping from the measured cabin response. The identification results indicate that the lowest damping ratio of the models is about 0.2%~0.4%. Friction-type cabin-cable joint seems to have main influence on the system damping.

The Oxidation State of Fe in Glasses from the Galapagos Archipelago: Variable Oxygen Fugacity as a Function of Mantle Source

NASA Astrophysics Data System (ADS)

Peterson, M. E.; Kelley, K. A.; Cottrell, E.; Saal, A. E.; Kurz, M. D.

2015-12-01

The oxidation state of the mantle plays an intrinsic role in the magmatic evolution of the Earth. Here we present new μ-XANES measurements of Fe3+/ΣFe ratios (a proxy for ƒO2) in a suite of submarine glasses from the Galapagos Archipelago. Using previously presented major, trace, and volatile elements and isotopic data for 4 groups of glass that come from distinct mantle sources (depleted upper mantle, 2 recycled, and a primitive mantle source) we show that Fe3+/ΣFe ratios vary both with the influence of shallow level processes and with variations in mantle source. Fe3+/ΣFe ratios increase with differentiation (i.e. decreasing MgO), but show a large variation at a given MgO. Progressive degassing of sulfur accompanies decreasing Fe3+/ΣFe ratios, while assimilation of hydrothermally altered crust (as indicated by increasing Sr/Sr*) is shown to increase Fe3+/ΣFe ratios. After taking these processes into account, there is still variability in the Fe3+/ΣFe ratios of the isotopically distinct sample suites studied, yielding a magmatic ƒO2 that ranges from ΔQFM = +0.16 to +0.74 (error < 0.5 log units) and showing that oxidation state varies as a function of mantle source composition in the Galapagos hotspot system. After correcting back to a common MgO content = 8.0 wt%, the trace element depleted group similar to MORB (ITD), and the group similar to Pinta (WD = high Th/La, Δ7/4, Δ8/4 ratios) show Fe3+/ΣFe ratios within the range of MORB (average ITD = 0.162 ± 0.003 and WD = 0.164 ± 0.006). Another trace element enriched group similar to Sierra Negra and Cerro Azul (ITE = enriched Sr and Pb isotopes) shows evidence of mixing between oxidized and reduced sources (ITE oxidized end-member = 0.177). This suggests that mantle sources in the Galapagos that are thought to contain recycled components (i.e., WD and ITE groups) have distinct oxidation states. The high 3He/4He Fernandina samples (HHe group) are shown to be the most oxidized (ave. 0.175 ± 0.006). With C/3He ratios an order of magnitude greater than MORB this suggests that the primitive mantle is a more carbonated and oxidized source than the depleted upper mantle.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adi, Y. A., E-mail: yudi.adi@math.uad.ac.id; Department of Mathematic Faculty of MIPA Universitas Gadjah Mada; Kusumo, F. A.

In this paper we consider a mathematical model of PI3K/AKT signaling pathways in phosphorylation AKT. PI3K/AKT pathway is an important mediator of cytokine signaling implicated in regulation of hematopoiesis. Constitutive activation of PI3K/AKT signaling pathway has been observed in Acute Meyloid Leukemia (AML) it caused by the mutation of Fms-like Tyrosine Kinase 3 in internal tandem duplication (FLT3-ITD), the most common molecular abnormality associated with AML. Depending upon its phosphorylation status, protein interaction, substrate availability, and localization, AKT can phosphorylate or inhibite numerous substrates in its downstream pathways that promote protein synthesis, survival, proliferation, and metabolism. Firstly, we present amore » mass action ordinary differential equation model describing AKT double phosphorylation (AKTpp) in a system with 11 equations. Finally, under the asumtion enzyme catalyst constant and steady state equilibrium, we reduce the system in 4 equation included Michaelis Menten constant. Simulation result suggested that a high concentration of PI3K and/or a low concentration of phospatase increased AKTpp activation. This result also indicates that PI3K is a potential target theraphy in AML.« less

A mathematical model of phosphorylation AKT in Acute Myeloid Leukemia

NASA Astrophysics Data System (ADS)

Adi, Y. A.; Kusumo, F. A.; Aryati, L.; Hardianti, M. S.

2016-04-01

In this paper we consider a mathematical model of PI3K/AKT signaling pathways in phosphorylation AKT. PI3K/AKT pathway is an important mediator of cytokine signaling implicated in regulation of hematopoiesis. Constitutive activation of PI3K/AKT signaling pathway has been observed in Acute Meyloid Leukemia (AML) it caused by the mutation of Fms-like Tyrosine Kinase 3 in internal tandem duplication (FLT3-ITD), the most common molecular abnormality associated with AML. Depending upon its phosphorylation status, protein interaction, substrate availability, and localization, AKT can phosphorylate or inhibite numerous substrates in its downstream pathways that promote protein synthesis, survival, proliferation, and metabolism. Firstly, we present a mass action ordinary differential equation model describing AKT double phosphorylation (AKTpp) in a system with 11 equations. Finally, under the asumtion enzyme catalyst constant and steady state equilibrium, we reduce the system in 4 equation included Michaelis Menten constant. Simulation result suggested that a high concentration of PI3K and/or a low concentration of phospatase increased AKTpp activation. This result also indicates that PI3K is a potential target theraphy in AML.

Cochlear implantation with hearing preservation yields significant benefit for speech recognition in complex listening environments

PubMed Central

Gifford, René H.; Dorman, Michael F.; Skarzynski, Henryk; Lorens, Artur; Polak, Marek; Driscoll, Colin L. W.; Roland, Peter; Buchman, Craig A.

2012-01-01

Objective The aim of this study was to assess the benefit of having preserved acoustic hearing in the implanted ear for speech recognition in complex listening environments. Design The current study included a within subjects, repeated-measures design including 21 English speaking and 17 Polish speaking cochlear implant recipients with preserved acoustic hearing in the implanted ear. The patients were implanted with electrodes that varied in insertion depth from 10 to 31 mm. Mean preoperative low-frequency thresholds (average of 125, 250 and 500 Hz) in the implanted ear were 39.3 and 23.4 dB HL for the English- and Polish-speaking participants, respectively. In one condition, speech perception was assessed in an 8-loudspeaker environment in which the speech signals were presented from one loudspeaker and restaurant noise was presented from all loudspeakers. In another condition, the signals were presented in a simulation of a reverberant environment with a reverberation time of 0.6 sec. The response measures included speech reception thresholds (SRTs) and percent correct sentence understanding for two test conditions: cochlear implant (CI) plus low-frequency hearing in the contralateral ear (bimodal condition) and CI plus low-frequency hearing in both ears (best aided condition). A subset of 6 English-speaking listeners were also assessed on measures of interaural time difference (ITD) thresholds for a 250-Hz signal. Results Small, but significant, improvements in performance (1.7 – 2.1 dB and 6 – 10 percentage points) were found for the best-aided condition vs. the bimodal condition. Postoperative thresholds in the implanted ear were correlated with the degree of EAS benefit for speech recognition in diffuse noise. There was no reliable relationship among measures of audiometric threshold in the implanted ear nor elevation in threshold following surgery and improvement in speech understanding in reverberation. There was a significant correlation between ITD threshold at 250 Hz and EAS-related benefit for the adaptive SRT. Conclusions Our results suggest that (i) preserved low-frequency hearing improves speech understanding for CI recipients (ii) testing in complex listening environments, in which binaural timing cues differ for signal and noise, may best demonstrate the value of having two ears with low-frequency acoustic hearing and (iii) preservation of binaural timing cues, albeit poorer than observed for individuals with normal hearing, is possible following unilateral cochlear implantation with hearing preservation and is associated with EAS benefit. Our results demonstrate significant communicative benefit for hearing preservation in the implanted ear and provide support for the expansion of cochlear implant criteria to include individuals with low-frequency thresholds in even the normal to near-normal range. PMID:23446225

Large Modal Survey Testing Using the Ibrahim Time Domain Identification Technique

NASA Technical Reports Server (NTRS)

Ibrahim, S. R.; Pappa, R. S.

1985-01-01

The ability of the ITD identification algorithm in identifying a complete set of structural modal parameters using a large number of free-response time histories simultaneously in one analysis, assuming a math model with a high number of degrees-of-freedom, has been studied. Identification results using simulated free responses of a uniform rectangular plate, with 225 measurement stations, and experimental responses from a ground vibration test of the Long Duration Exposure Facility (LDEF) Space Shuttle payload, with 142 measurement stations, are presented. As many as 300 degrees-of-freedom were allowed in analyzing these data. In general, the use of a significantly oversized math model in the identification process was found to maintain or increase identification accuracy and to identify modes of low response level that are not identified with smaller math model sizes. The concept of a Mode Shape Correlation Constant is introduced for use when more than one identification analysis of the same structure are conducted. This constant quantifies the degree of correlation between any two sets of complex mode shapes identified using different excitation conditions, different user-selectable algorithm constants, or overlapping sets of measurements.

Synergism of Curcumin and Cytarabine in the Down Regulation of Multi-Drug Resistance Genes in Acute Myeloid Leukemia.

PubMed

Shah, Krupa; Mirza, Sheefa; Desai, Urja; Jain, Nayan; Rawal, Rakesh

2016-01-01

The aim of the study was to find a role of Curcumin from natural source to overcome drug resistance as well as to reduce cytotoxicity profile of the drug in Acute Myeloid Leukemia patients. Primary leukemic cells were obtained from AML patient's bone marrow. These cells were then exposed to different concentration of cytarabine and curcumin to find out IC50 values and also its effect on MDR genes like MDR1, BCRP, LRP and FLT3 by RT-PCR method. Our results suggested that curcumin down regulates MDR genes. Gene expression was decreased by 35.75, 31.30, 27.97 % for MDR1, LRP, BCRP respectively. In FLT3, it was 65.86 % for wild type and 31.79 % for FLT3-ITD. In addition to this, curcumin has also shown anti-proliferative effect as well as synergistic effect in combination with Cytarabine on primary leukemic cells. Thus, we can conclude that curcumin can be used as MDR modulator as well as chemosensitizer in combination with cytarabine, standard chemotherapeutic drug, to reduce the cytotoxicity profile as IC50 value decreases when treated in combination.

Expression of HOXB genes is significantly different in acute myeloid leukemia with a partial tandem duplication of MLL vs. a MLL translocation: a cross-laboratory study.

PubMed

Liu, Hsi-Che; Shih, Lee-Yung; May Chen, Mei-Ju; Wang, Chien-Chih; Yeh, Ting-Chi; Lin, Tung-Huei; Chen, Chien-Yu; Lin, Chih-Jen; Liang, Der-Cherng

2011-05-01

In acute myeloid leukemia (AML), the mixed lineage leukemia (MLL) gene may be rearranged to generate a partial tandem duplication (PTD), or fused to partner genes through a chromosomal translocation (tMLL). In this study, we first explored the differentially expressed genes between MLL-PTD and tMLL using gene expression profiling of our cohort (15 MLL-PTD and 10 tMLL) and one published data set. The top 250 probes were chosen from each set, resulting in 29 common probes (21 unique genes) to both sets. The selected genes include four HOXB genes, HOXB2, B3, B5, and B6. The expression values of these HOXB genes significantly differ between MLL-PTD and tMLL cases. Clustering and classification analyses were thoroughly conducted to support our gene selection results. Second, as MLL-PTD, FLT3-ITD, and NPM1 mutations are identified in AML with normal karyotypes, we briefly studied their impact on the HOXB genes. Another contribution of this study is to demonstrate that using public data from other studies enriches samples for analysis and yields more conclusive results. 2011 Elsevier Inc. All rights reserved.

Advances in clinical studies of cardiopulmonary resuscitation

PubMed Central

Chen, Shou-quan

2015-01-01

BACKGROUND: The survival rate of patients after cardiac arrest (CA) remains lower since 2010 International Consensus on Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC) was published. In clinical trials, the methods and techniques for CPR have been overly described. This article gives an overview of the progress in methods and techniques for CPR in the past years. DATA SOURCES: Original articles about cardiac arrest and CPR from MEDLINE (PubMed) and relevant journals were searched, and most of them were clinical randomized controlled trials (RCTs). RESULTS: Forty-two articles on methods and techniques of CPR were reviewed, including chest compression and conventional CPR, chest compression depth and speed, defibrillation strategies and priority, mechanical and manual chest compression, advanced airway management, impedance threshold device (ITD) and active compression-decompression (ACD) CPR, epinephrine use, and therapeutic hypothermia. The results of studies and related issues described in the international guidelines had been testified. CONCLUSIONS: Although large multicenter studies on CPR are still difficult to carry out, progress has been made in the past 4 years in the methods and techniques of CPR. The results of this review provide evidences for updating the 2015 international guidelines. PMID:26056537

Protein Profiling Identifies mTOR Pathway Modulation and Cytostatic Effects of Pim Kinase Inhibitor, AZD1208, in Acute Myeloid Leukemia

PubMed Central

Chen, Lisa S.; Yang, Ji-Yeon; Liang, Han; Cortes, Jorge E.; Gandhi, Varsha

2017-01-01

Pim kinases phosphorylate and regulate a number of key AML cell survival proteins, and Pim inhibitors have recently entered clinical trial for hematological malignancies. AZD1208 is a small molecule pan-Pim kinase inhibitor and AZD1208 treatment resulted in growth inhibition and cell size reduction in AML cell lines including FLT3-WT (OCI-AML-3, KG-1a, MOLM-16) and FLT3-ITD mutated (MOLM-13, MV-4-11). There was limited apoptosis induction (<10% increase) in the AML cell lines evaluated with up to 3 μM AZD1208 for 24h, suggesting that growth inhibition is not through apoptosis induction. Using reverse phase protein array (RPPA) and immunoblot analysis, we identified that AZD1208 resulted in suppression of mTOR signaling, including inhibition of protein phosphorylation of mTOR(Ser2448), p70S6K(Thr389), S6(Ser235/236) and 4E-BP1(Ser65). Consistent with mTOR inhibition, there was also a reduction in protein synthesis that correlated with cell size reduction and growth inhibition with AZD1208; our study provide insights into the mechanism of AZD1208. PMID:27054578

Inhibition of FLT3 Expression by Green Tea Catechins in FLT3 Mutated-AML Cells

PubMed Central

Ly, Bui Thi Kim; Chi, Hoang Thanh; Yamagishi, Makoto; Kano, Yasuhiko; Hara, Yukihiko; Nakano, Kazumi; Sato, Yuko; Watanabe, Toshiki

2013-01-01

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a block in differentiation and uncontrolled proliferation. FLT3 is a commonly mutated gene found in AML patients. In clinical trials, the presence of a FLT3-ITD mutation significantly correlates with an increased risk of relapse and dismal overall survival. Therefore, activated FLT3 is a promising molecular target for AML therapies. In this study, we have shown that green tea polyphenols including (−)-epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), and (−)-epicatechin-3-gallate (ECG) suppress the proliferation of AML cells. Interestingly, EGCG, EGC and ECG showed the inhibition of FLT3 expression in cell lines harboring FLT3 mutations. In the THP-1 cells harboring FLT3 wild-type, EGCG showed the suppression of cell proliferation but did not suppress the expression of FLT3 even at the concentration that suppress 100% cell proliferation. Moreover, EGCG-, EGC-and ECG-treated cells showed the suppression of MAPK, AKT and STAT5 phosphorylation. Altogether, we suggest that green tea polyphenols could serve as reagents for treatment or prevention of leukemia harboring FLT3 mutations. PMID:23840454

Targeting HSP90 dimerization via the C-terminus is effective in imatinib resistant CML and lacks heat shock response.

PubMed

Bhatia, Sanil; Diedrich, Daniela; Frieg, Benedikt; Ahlert, Heinz; Stein, Stefan; Bopp, Bertan; Lang, Franziska; Zang, Tao; Kröger, Tobias; Ernst, Thomas; Kögler, Gesine; Krieg, Andreas; Lüdeke, Steffen; Kunkel, Hana; Rodrigues Moita, Ana J; Kassack, Matthias U; Marquardt, Viktoria; Opitz, Friederike V; Oldenburg, Marina; Remke, Marc; Babor, Florian; Grez, Manuel; Hochhaus, Andreas; Borkhardt, Arndt; Groth, Georg; Nagel-Steger, Luitgard; Jose, Joachim; Kurz, Thomas; Gohlke, Holger; Hansen, Finn K; Hauer, Julia

2018-05-03

Heat shock protein 90 (HSP90) stabilizes many client proteins including BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of CML in which treatment-free remission (TFR) is limited with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics, which synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain (NTD) of HSP90 are under investigation; however, side effects such as induction of heat shock response (HSR) and toxicity have so far precluded their FDA approval. We have developed a novel inhibitor (referred to as aminoxyrone) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain (CTD). This was achieved by structure-based molecular design, chemical synthesis, and functional pre-clinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. Aminoxyrone (AX) is a promising potential candidate, which induces apoptosis in leukemic stem cells (LSCs) fraction (CD34 + CD38 - ) as well as the leukemic bulk (CD34 + CD38 + ) of primary CML and in TKI-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated and targeting HSP90 C-terminus by AX does not induce HSR in vitro and in vivo. We also probed the potential of AX in other therapy refractory leukemia such as BCR-ABL1+ BCP-ALL, FLT3-ITD+ AML and Ph-like BCP-ALL. Therefore, AX is the first peptidometic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other therapy-refractory leukemia, due to its low toxicity profile and lack of HSR. Copyright © 2018 American Society of Hematology.

The across frequency independence of equalization of interaural time delay in the equalization-cancellation model of binaural unmasking.

PubMed

Akeroyd, Michael A

2004-08-01

The equalization stage in the equalization-cancellation model of binaural unmasking compensates for the interaural time delay (ITD) of a masking noise by introducing an opposite, internal delay [N. I. Durlach, in Foundations of Modern Auditory Theory, Vol. II., edited by J. V. Tobias (Academic, New York, 1972)]. Culling and Summerfield [J. Acoust. Soc. Am. 98, 785-797 (1995)] developed a multi-channel version of this model in which equalization was "free" to use the optimal delay in each channel. Two experiments were conducted to test if equalization was indeed free or if it was "restricted" to the same delay in all channels. One experiment measured binaural detection thresholds, using an adaptive procedure, for 1-, 5-, or 17-component tones against a broadband masking noise, in three binaural configurations (N0S180, N180S0, and N90S270). The thresholds for the 1-component stimuli were used to normalize the levels of each of the 5- and 17-component stimuli so that they were equally detectable. If equalization was restricted, then, for the 5- and 17-component stimuli, the N90S270 and N180S0 configurations would yield a greater threshold than the N0S180 configurations. No such difference was found. A subsequent experiment measured binaural detection thresholds, via psychometric functions, for a 2-component complex tone in the same three binaural configurations. Again, no differential effect of configuration was observed. An analytic model of the detection of a complex tone showed that the results were more consistent with free equalization than restricted equalization, although the size of the differences was found to depend on the shape of the psychometric function for detection.

Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet?

PubMed

Chung, Clement; Ma, Hilary

2017-09-01

Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not changed significantly over the last few decades. We present a nonexhaustive summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies that depart significantly from conventional chemotherapy, the current mainstay for the treatment of acute leukemias. Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia and PML-RARα for acute promyelocytic leukemia. Evidence indicates that targeted therapy for FLT-ITD gene mutations with small-molecule tyrosine kinase inhibitors can extend its use from relapsed disease to up-front induction therapy. Core-binding factor acute myeloid leukemia in adults predicts benefit with high-dose cytarabine in the absence of KIT mutation. Although risk-adapted therapy based on genetic abnormalities in acute leukemias has allowed the beginning of personalized treatment and selective use of hematopoietic stem cell transplantation, the prognostic and/or predictive value of many novel mutations of the acute leukemic genome is yet to be elucidated. Many challenges lie ahead in targeted therapies due to overlapping of chromosomal and molecular lesions as well as other limiting factors. Future work should focus on the understanding of pathogenetic changes that lead to leukemogenesis, which may guide the rational design of new targeted therapies and make the drive toward precision medicine for acute leukemias one step closer. © 2017 Pharmacotherapy Publications, Inc.

PRL-3, a Metastasis Associated Tyrosine Phosphatase, Is Involved in FLT3-ITD Signaling and Implicated in Anti-AML Therapy

PubMed Central

Zhou, Jianbiao; Bi, Chonglei; Chng, Wee-Joo; Cheong, Lip-Lee; Liu, Shaw-Cheng; Mahara, Sylvia; Tay, Kian-Ghee; Zeng, Qi; Li, Jie; Guo, Ke; Tan, Cheng Peow Bobby; Yu, Hanry; Albert, Daniel H.; Chen, Chien-Shing

2011-01-01

Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL-3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation. PMID:21589872

A new Leukemia Prognostic Scoring System for refractory/relapsed adult acute myelogeneous leukaemia patients: a GOELAMS study.

PubMed

Chevallier, P; Labopin, M; Turlure, P; Prebet, T; Pigneux, A; Hunault, M; Filanovsky, K; Cornillet-Lefebvre, P; Luquet, I; Lode, L; Richebourg, S; Blanchet, O; Gachard, N; Vey, N; Ifrah, N; Milpied, N; Harousseau, J-L; Bene, M-C; Mohty, M; Delaunay, J

2011-06-01

A simplified prognostic score is presented based on the multivariate analysis of 138 refractory/relapsed acute myeloid leukaemia (AML) patients (median age 55 years, range: 19-70) receiving a combination of intensive chemotherapy+Gemtuzumab as salvage regimen. Overall, 2-year event-free survival (EFS) and overall survival (OS) were 29±4% and 36±4%, respectively. Disease status (relapse <12 months, including refractory patients), FLT3-ITD-positive status and high-risk cytogenetics were the three strongest independent adverse prognostic factors for OS and EFS in this series. We then defined three subgroups with striking different outcomes at 2 years: no adverse factor (favourable, N=36): OS 58%, EFS 45%; one adverse factor (intermediate, N=54): OS 37%, EFS 31%; two or three adverse factors (poor, N=43): OS 12%, EFS 12% (P<10(-4), P=0.001). This new simplified Leukemia Prognostic Scoring System was then validated on an independent cohort of 111 refractory/relapsed AML patients. This new simplified prognostic score, using three clinical and biological parameters routinely applied, allow to discriminate around two third of the patients who should benefit from a salvage intensive regimen in the setting of refractory/relapsed AML patients. The other one third of the patients should receive investigational therapy.

Cortical Transformation of Spatial Processing for Solving the Cocktail Party Problem: A Computational Model123

PubMed Central

Dong, Junzi; Colburn, H. Steven

2016-01-01

In multisource, “cocktail party” sound environments, human and animal auditory systems can use spatial cues to effectively separate and follow one source of sound over competing sources. While mechanisms to extract spatial cues such as interaural time differences (ITDs) are well understood in precortical areas, how such information is reused and transformed in higher cortical regions to represent segregated sound sources is not clear. We present a computational model describing a hypothesized neural network that spans spatial cue detection areas and the cortex. This network is based on recent physiological findings that cortical neurons selectively encode target stimuli in the presence of competing maskers based on source locations (Maddox et al., 2012). We demonstrate that key features of cortical responses can be generated by the model network, which exploits spatial interactions between inputs via lateral inhibition, enabling the spatial separation of target and interfering sources while allowing monitoring of a broader acoustic space when there is no competition. We present the model network along with testable experimental paradigms as a starting point for understanding the transformation and organization of spatial information from midbrain to cortex. This network is then extended to suggest engineering solutions that may be useful for hearing-assistive devices in solving the cocktail party problem. PMID:26866056

Accounting for binaural detection as a function of masker interaural correlation: effects of center frequency and bandwidth.

PubMed

Bernstein, Leslie R; Trahiotis, Constantine

2014-12-01

Binaural detection was measured as a function of the center frequency, bandwidth, and interaural correlation of masking noise. Thresholds were obtained for 500-Hz or 125-Hz Sπ tonal signals and for the latter stimuli (noise or signal-plus-noise) transposed to 4 kHz. A primary goal was assessment of the generality of van der Heijden and Trahiotis' [J. Acoust. Soc. Am. 101, 1019-1022 (1997)] hypothesis that thresholds could be accounted for by the "additive" masking effects of the underlying No and Nπ components of a masker having an interaural correlation of ρ. Results indicated that (1) the overall patterning of the data depended neither upon center frequency nor whether information was conveyed via the waveform or by its envelope; (2) thresholds for transposed stimuli improved relative to their low-frequency counterparts as bandwidth of the masker was increased; (3) the additivity approach accounted well for the data across stimulus conditions but consistently overestimated MLDs, especially for narrowband maskers; (4) a quantitative approach explicitly taking into account the distributions of time-varying ITD-based lateral positions produced by masker-alone and signal-plus-masker waveforms proved more successful, albeit while employing a larger set of assumptions, parameters, and computational complexity.

Impact of monaural frequency compression on binaural fusion at the brainstem level.

PubMed

Klauke, Isabelle; Kohl, Manuel C; Hannemann, Ronny; Kornagel, Ulrich; Strauss, Daniel J; Corona-Strauss, Farah I

2015-08-01

A classical objective measure for binaural fusion at the brainstem level is the so-called β-wave of the binaural interaction component (BIC) in the auditory brainstem response (ABR). However, in some cases it appeared that a reliable detection of this component still remains a challenge. In this study, we investigate the wavelet phase synchronization stability (WPSS) of ABR data for the analysis of binaural fusion and compare it to the BIC. In particular, we examine the impact of monaural nonlinear frequency compression on binaural fusion. As the auditory system is tonotopically organized, an interaural frequency mismatch caused by monaural frequency compression could negatively effect binaural fusion. In this study, only few subjects showed a detectable β-wave and in most cases only for low ITDs. However, we present a novel objective measure for binaural fusion that outperforms the current state-of-the-art technique (BIC): the WPSS analysis showed a significant difference between the phase stability of the sum of the monaurally evoked responses and the phase stability of the binaurally evoked ABR. This difference could be an indicator for binaural fusion in the brainstem. Furthermore, we observed that monaural frequency compression could indeed effect binaural fusion, as the WPSS results for this condition vary strongly from the results obtained without frequency compression.

Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

ClinicalTrials.gov

2017-12-11

Acute Biphenotypic Leukemia; Acute Erythroid Leukemia in Remission; Acute Leukemia in Remission; Acute Megakaryoblastic Leukemia; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia in Remission; Acute Myeloid Leukemia With FLT3/ITD Mutation; Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2) or t(3;3) (q21.3;q26.2); GATA2, MECOM; Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2); GATA2, MECOM; Acute Myeloid Leukemia With Multilineage Dysplasia; Acute Myeloid Leukemia With t(6;9) (p23;q34.1); DEK-NUP214; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Complete Remission; B Acute Lymphoblastic Leukemia With t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1); B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1; Burkitt Lymphoma; Childhood Acute Lymphoblastic Leukemia in Complete Remission; DS Stage II Plasma Cell Myeloma; DS Stage III Plasma Cell Myeloma; Myelodysplastic Syndrome; Recurrent Anaplastic Large Cell Lymphoma; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma; Secondary Acute Myeloid Leukemia; T Lymphoblastic Lymphoma

Cortical Transformation of Spatial Processing for Solving the Cocktail Party Problem: A Computational Model(1,2,3).

PubMed

Dong, Junzi; Colburn, H Steven; Sen, Kamal

2016-01-01

In multisource, "cocktail party" sound environments, human and animal auditory systems can use spatial cues to effectively separate and follow one source of sound over competing sources. While mechanisms to extract spatial cues such as interaural time differences (ITDs) are well understood in precortical areas, how such information is reused and transformed in higher cortical regions to represent segregated sound sources is not clear. We present a computational model describing a hypothesized neural network that spans spatial cue detection areas and the cortex. This network is based on recent physiological findings that cortical neurons selectively encode target stimuli in the presence of competing maskers based on source locations (Maddox et al., 2012). We demonstrate that key features of cortical responses can be generated by the model network, which exploits spatial interactions between inputs via lateral inhibition, enabling the spatial separation of target and interfering sources while allowing monitoring of a broader acoustic space when there is no competition. We present the model network along with testable experimental paradigms as a starting point for understanding the transformation and organization of spatial information from midbrain to cortex. This network is then extended to suggest engineering solutions that may be useful for hearing-assistive devices in solving the cocktail party problem.

Extracting binaural information from simultaneous targets and distractors: Effects of amplitude modulation and asynchronous envelopes

PubMed Central

Stellmack, Mark A.; Byrne, Andrew J.; Viemeister, Neal F.

2010-01-01

When different components of a stimulus carry different binaural information, processing of binaural information in a target component is often affected. The present experiments examine whether such interference is affected by amplitude modulation and the relative phase of modulation of the target and distractors. In all experiments, listeners attempted to discriminate interaural time differences of a target stimulus in the presence of distractor stimuli with ITD=0. In Experiment 1, modulation of the distractors but not the target reduced interference between components. In Experiment 2, synthesized musical notes exhibited little binaural interference when there were slight asynchronies between different streams of notes (31 or 62 ms). The remaining experiments suggested that the reduction in binaural interference in the previous experiments was due neither to the complex spectra of the synthesized notes nor to greater detectability of the target in the presence of modulated distractors. These data suggest that this interference is reduced when components are modulated in ways that result in the target appearing briefly in isolation, not because of segregation cues. These data also suggest that modulation and asynchronies between modulators that might be encountered in real-world listening situations are adequate to reduce binaural interference to inconsequential levels. PMID:20815459

Cost, Time, and Risk Assessment of Different Wave Energy Converter Technology Development Trajectories: Preprint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weber, Jochem W; Laird, Daniel; Costello, Ronan

This paper presents a comparative assessment of three fundamentally different wave energy converter technology development trajectories. The three technology development trajectories are expressed and visualised as a function of technology readiness levels and technology performance levels. The assessment shows that development trajectories that initially prioritize technology readiness over technology performance are likely to require twice the development time, consume a threefold of the development cost, and are prone to a risk of technical or commercial failure of one order of magnitude higher than those development trajectories that initially prioritize technology performance over technology readiness.

Petrogenesis of Neoarchean metavolcanic rocks in Changyukou, Northwestern Hebei: Implications for the transition stage from a compressional to an extensional regime for the North China Craton

NASA Astrophysics Data System (ADS)

Liou, Peng; Shan, Houxiang; Liu, Fu; Guo, Jinghui

2017-03-01

The 2.5 Ga metavolcanic rocks in Changyukou, Northwestern Hebei, can be classified into three groups based on major and trace elements: high-Mg basalts, tholeiitic basalts, and the calc-alkaline series (basaltic andesites-andesites and dacites-rhyolites). Both high-Mg basalts and tholeiitic basalts have negative anomalies of Nb, Zr, Ti and Heavy Rare Earth Elements (HREE) as well as enrichments of Sr, K, Pb, Ba and Light Rare Earth Elements (LREE) and show typical subduction zone affinities. The petrogenesis of high-Mg basalts can be ascribed to high-degree partial melting of an enriched mantle source in the spinel stability field that was previously enriched in Large Ion Lithophile Elements (LILE) and LREE by slab-derived hydrous fluids/melts/supercritical fluids, as well as the subsequent magma mixing processes of different sources at different source depths, with little or no influence of polybaric fractional crystallization. The flat HREE of tholeiitic basalts indicates they may also originate from the spinel stability field, but from obviously shallower depths than the source of high-Mg basalts. They may form at a later stage of the subduction process when rapid slab rollback leads to extension and seafloor spreading in the upper plate. We obtain the compositions of the Archean lower crust of the North China Craton based on the Archean Wutai-Jining section by compiling the average tonalite-trondhjemite-granodiorite (TTG) components, average mafic granulite components, and average sedimentary rock components. The modeling results show that the generation of high-Al basalts, basaltic andesites and andesites can be attributed to assimilation by high-Mg basalts (primary basalts) of relatively high-Al2O3 thickened lower crust and the subsequent crystallization of prevailing mafic mineral phases, while Al2O3-rich plagioclase crystallization is suppressed under high-pressure and nearly water-saturated conditions. Dacites and rhyolites may be the result of further fractional crystallization of basaltic andesites (high-Al basalts) and andesites. Mixing of magmas at various stages along the fractionation course of basaltic andesites (high-Al basalts) toward rhyolites promotes the trend of the calc-alkaline series. To reconcile the 2.55 to 2.5 Ga TTGs derived from overthickened crust, the 2.51 to 2.50 Ga calc-alkaline volcanic rocks derived from thickened crust, tholeiitic basalts representing low pressure and an extensional tectonic setting, 2493 Ma leucosyenogranites derived from overthickened crust, 2437 Ma biotite-monzogranites derived from slightly thinner crust than leucosyenogranites but still thickened, as well as the clockwise hybrid ITD and IBC P-T paths of the HP granulites and widespread extension and rifting setting within the NCC from 2300 Ma, we propose a model of an evolving subduction process. Among them, the composition of the 2.5 Ga Changyukou volcanic rocks and potassic granites as well as the clockwise hybrid ITD and IBC P-T paths of the HP granulites may reveal that the tectonic setting in Northwest Hebei was in a transition stage from a subduction-related compressional regime to an extensional regime related to plate rollback.

Evaluating the Usefulness of High-Temporal Resolution Vegetation Indices to Identify Crop Types

NASA Astrophysics Data System (ADS)

Hilbert, K.; Lewis, D.; O'Hara, C. G.

2006-12-01

The National Aeronautical and Space Agency (NASA) and the United States Department of Agriculture (USDA) jointly sponsored research covering the 2004 to 2006 South American crop seasons that focused on developing methods for the USDA's Foreign Agricultural Service's (FAS) Production Estimates and Crop Assessment Division (PECAD) to identify crop types using MODIS-derived, hyper-temporal Normalized Difference Vegetation Index (NDVI) images. NDVI images were composited in 8 day intervals from daily NDVI images and aggregated to create a hyper-termporal NDVI layerstack. This NDVI layerstack was used as input to image classification algorithms. Research results indicated that creating high-temporal resolution Normalized Difference Vegetation Index (NDVI) composites from NASA's MODerate Resolution Imaging Spectroradiometer (MODIS) data products provides useful input to crop type classifications as well as potential useful input for regional crop productivity modeling efforts. A current NASA-sponsored Rapid Prototyping Capability (RPC) experiment will assess the utility of simulated future Visible Infrared Imager / Radiometer Suite (VIIRS) imagery for conducting NDVI-derived land cover and specific crop type classifications. In the experiment, methods will be considered to refine current MODIS data streams, reduce the noise content of the MODIS, and utilize the MODIS data as an input to the VIIRS simulation process. The effort also is being conducted in concert with an ISS project that will further evaluate, verify and validate the usefulness of specific data products to provide remote sensing-derived input for the Sinclair Model a semi-mechanistic model for estimating crop yield. The study area encompasses a large portion of the Pampas region of Argentina--a major world producer of crops such as corn, soybeans, and wheat which makes it a competitor to the US. ITD partnered with researchers at the Center for Surveying Agricultural and Natural Resources (CREAN) of the National University of Cordoba, Argentina, and CREAN personnel collected and continue to collect field-level, GIS-based in situ information. Current efforts involve both developing and optimizing software tools for the necessary data processing. The software includes the Time Series Product Tool (TSPT), Leica's ERDAS Imagine, and Mississippi State University's Temporal Map Algebra computational tools.

WE-G-213CD-06: Implementation of Real-Time Tumor Tracking Using Robotic Couch.

PubMed

Buzurovic, I; Yu, Y; Podder, T

2012-06-01

The purpose of this study was to present a novel method for real- time tumor tracking using a commercially available robotic treatment couch, and to evaluate tumor tracking accuracy. Commercially available robotic couches are capable of positioning patients with high level of accuracy; however, currently there is no provision for compensating tumor motion using these systems. Elekta's existing commercial couch (PreciseTM Table) was used without changing its design. To establish the real-time couch motion for tracking, a novel control system was developed and implemented. The tabletop could be moved in horizontal plane (laterally and longitudinally) using two Maxon-24V motors with gearbox combination. Vertical motion was obtained using robust 70V-Rockwell Automation motor. For vertical motor position sensing, we used Model 755A-Accu- Coder encoder. Two Baumer-ITD_01_4mm shaft encoders were used for the lateral and longitudinal motions of the couch. Motors were connected to the Advance Motion Controls (AMC) amplifiers: for the vertical motion, motor AMC-20A20-INV amplifier was used, and two AMC-Z6A8 amplifiers were applied for the lateral and longitudinal couch motions. The Galil DMC-4133 controller was connected to standard PC computer using USB port. The system had two independent power supplies: Galil PSR-12- 24-12A, 24vdc power supply with diodes for controller and 24vdc motors and amplifiers, and Galil-PS300W72 72vdc power supply for vertical motion. Control algorithms were developed for position and velocity adjustment. The system was tested for real-time tracking in the range of 50mm in all 3 directions (superior-inferior, lateral, anterior- posterior). Accuracies were 0.15, 0.20, and 0.18mm, respectively. Repeatability of the desired motion was within ± 0.2mm. Experimental results of couch tracking show feasibility of real-time tumor tracking with high level of accuracy (within sub-millimeter range). This tracking technique potentially offers a simple and effective method to minimize healthy tissues irradiation.Acknowledgement: Study supported by Elekta,Ltd. Study supported by Elekta, Ltd. © 2012 American Association of Physicists in Medicine.

Bilateral cochlear implants in children: Effects of auditory experience and deprivation on auditory perception

PubMed Central

Litovsky, Ruth Y.; Gordon, Karen

2017-01-01

Spatial hearing skills are essential for children as they grow, learn and play. They provide critical cues for determining the locations of sources in the environment, and enable segregation of important sources, such as speech, from background maskers or interferers. Spatial hearing depends on availability of monaural cues and binaural cues. The latter result from integration of inputs arriving at the two ears from sounds that vary in location. The binaural system has exquisite mechanisms for capturing differences between the ears in both time of arrival and intensity. The major cues that are thus referred to as being vital for binaural hearing are: interaural differences in time (ITDs) and interaural differences in levels (ILDs). In children with normal hearing (NH), spatial hearing abilities are fairly well developed by age 4–5 years. In contrast, children who are deaf and hear through cochlear implants (CIs) do not have an opportunity to experience normal, binaural acoustic hearing early in life. These children may function by having to utilize auditory cues that are degraded with regard to numerous stimulus features. In recent years there has been a notable increase in the number of children receiving bilateral CIs, and evidence suggests that while having two CIs helps them function better than when listening through a single CI, they generally perform worse than their NH peers. This paper reviews some of the recent work on bilaterally implanted children. The focus is on measures of spatial hearing, including sound localization, release from masking for speech understanding in noise and binaural sensitivity using research processors. Data from behavioral and electrophysiological studies are included, with a focus on the recent work of the authors and their collaborators. The effects of auditory plasticity and deprivation on the emergence of binaural and spatial hearing are discussed along with evidence for reorganized processing from both behavioral and electrophysiological studies. The consequences of both unilateral and bilateral auditory deprivation during development suggest that the relevant set of issues is highly complex with regard to successes and the limitations experienced by children receiving bilateral cochlear implants. PMID:26828740

NASA's Microgravity Technology Report, 1996: Summary of Activities

NASA Technical Reports Server (NTRS)

Kierk, Isabella

1996-01-01

This report covers technology development and technology transfer activities within the Microgravity Science Research Programs during FY 1996. It also describes the recent major tasks under the Advanced Technology Development (ATD) Program and identifies current technology requirements. This document is consistent with NASA,s Enteprise for the Human Exploration and development of Space (HEDS) Strategic Plan. This annual update reflects changes in the Microgravity Science Research Program's new technology activities and requirements. Appendix A. FY 1996 Advanced Technology Development. Program and Project Descriptions. Appendix B. Technology Development.

NASA/Goddard Thermal Technology Overview 2014

NASA Technical Reports Server (NTRS)

Butler, Daniel; Swanson, Theodore D.

2014-01-01

This presentation summarizes the current plans and efforts at NASA Goddard to develop new thermal control technology for anticipated future missions. It will also address some of the programmatic developments currently underway at NASA, especially with respect to the Technology Development Program at NASA. While funding for basic technology development is still scarce, significant efforts are being made in direct support of flight programs. New technology development continues to be driven by the needs of future missions, and applications of these technologies to current Goddard programs will be addressed. Many of these technologies also have broad applicability to DOD, DOE, and commercial programs. Partnerships have been developed with the Air Force, Navy, and various universities to promote technology development. In addition, technology development activities supported by internal research and development (IRAD) program, the Small Business Innovative Research (SBIR) program, and the NASA Engineering and Safety Center (NESC), are reviewed in this presentation. Specific technologies addressed include; two-phase systems applications and issues on NASA missions, latest developments of electro-hydrodynamically pumped systems, development of high electrical conductivity coatings, and various other research activities. New Technology program underway at NASA, although funding is limited center dot NASA/GSFC's primary mission of science satellite development is healthy and vibrant, although new missions are scarce - now have people on overhead working new missions and proposals center dot Future mission applications promise to be thermally challenging center dot Direct technology funding is still very restricted - Projects are the best source for direct application of technology - SBIR thermal subtopic resurrected in FY 14 - Limited Technology development underway via IRAD, NESC, other sources - Administrator pushing to revive technology and educational programs at NASA - new HQ directorate established

Technology CAD for integrated circuit fabrication technology development and technology transfer

NASA Astrophysics Data System (ADS)

Saha, Samar

2003-07-01

In this paper systematic simulation-based methodologies for integrated circuit (IC) manufacturing technology development and technology transfer are presented. In technology development, technology computer-aided design (TCAD) tools are used to optimize the device and process parameters to develop a new generation of IC manufacturing technology by reverse engineering from the target product specifications. While in technology transfer to manufacturing co-location, TCAD is used for process centering with respect to high-volume manufacturing equipment of the target manufacturing equipment of the target manufacturing facility. A quantitative model is developed to demonstrate the potential benefits of the simulation-based methodology in reducing the cycle time and cost of typical technology development and technology transfer projects over the traditional practices. The strategy for predictive simulation to improve the effectiveness of a TCAD-based project, is also discussed.

A summary of the status of biomass conversion technologies and opportunities for their use in developing countries

NASA Astrophysics Data System (ADS)

Waddle, D. B.; Perlack, R. D.; Wimberly, J.

Biomass plays a significant role in energy use in developing countries: however, these resources are often used very inefficiently. Recent technology developments have made possible improved conversion efficiencies for utility scale technologies. These developments may be of interest in the wake of recent policy changes occurring in several developing countries, with respect to independent power production. Efforts are also being directed at developing biomass conversion technologies that can interface and/or compete with internal combustion engines for small, isolated loads. The technological status is reviewed of biomass conversion technologies appropriate for commercial, industrial, and small utility applications in developing countries. Market opportunities, constraints, and technology developments are also discussed.

Technology Estimating 2: A Process to Determine the Cost and Schedule of Space Technology Research and Development

NASA Technical Reports Server (NTRS)

Cole, Stuart K.; Wallace, Jon; Schaffer, Mark; May, M. Scott; Greenberg, Marc W.

2014-01-01

As a leader in space technology research and development, NASA is continuing in the development of the Technology Estimating process, initiated in 2012, for estimating the cost and schedule of low maturity technology research and development, where the Technology Readiness Level is less than TRL 6. NASA' s Technology Roadmap areas consist of 14 technology areas. The focus of this continuing Technology Estimating effort included four Technology Areas (TA): TA3 Space Power and Energy Storage, TA4 Robotics, TA8 Instruments, and TA12 Materials, to confine the research to the most abundant data pool. This research report continues the development of technology estimating efforts completed during 2013-2014, and addresses the refinement of parameters selected and recommended for use in the estimating process, where the parameters developed are applicable to Cost Estimating Relationships (CERs) used in the parametric cost estimating analysis. This research addresses the architecture for administration of the Technology Cost and Scheduling Estimating tool, the parameters suggested for computer software adjunct to any technology area, and the identification of gaps in the Technology Estimating process.

A study of mass data storage technology for rocket engine data

NASA Technical Reports Server (NTRS)

Ready, John F.; Benser, Earl T.; Fritz, Bernard S.; Nelson, Scott A.; Stauffer, Donald R.; Volna, William M.

1990-01-01

The results of a nine month study program on mass data storage technology for rocket engine (especially the Space Shuttle Main Engine) health monitoring and control are summarized. The program had the objective of recommending a candidate mass data storage technology development for rocket engine health monitoring and control and of formulating a project plan and specification for that technology development. The work was divided into three major technical tasks: (1) development of requirements; (2) survey of mass data storage technologies; and (3) definition of a project plan and specification for technology development. The first of these tasks reviewed current data storage technology and developed a prioritized set of requirements for the health monitoring and control applications. The second task included a survey of state-of-the-art and newly developing technologies and a matrix-based ranking of the technologies. It culminated in a recommendation of optical disk technology as the best candidate for technology development. The final task defined a proof-of-concept demonstration, including tasks required to develop, test, analyze, and demonstrate the technology advancement, plus an estimate of the level of effort required. The recommended demonstration emphasizes development of an optical disk system which incorporates an order-of-magnitude increase in writing speed above the current state of the art.

An Analysis of the Relationship between Professional Development, School Leadership, Technology Infrastructure, and Technology Use

ERIC Educational Resources Information Center

Mishnick, Nicole

2017-01-01

This dissertation study investigates the relationship between professional development, school leadership, technology infrastructure and technology use. Three research questions were developed. The first examines the relationship between professional development and technology use, the second examines the relationship between school leadership and…

The Status of Spacecraft Bus and Platform Technology Development Under the NASA ISPT Program

NASA Technical Reports Server (NTRS)

Anderson, David; Munk, Michelle M.; Pencil, Eric; Dankanich, John; Glaab, Louis; Peterson, Todd

2014-01-01

The In-Space Propulsion Technology (ISPT) program is developing spacecraft bus and platform technologies that will enable or enhance NASA robotic science missions. The ISPT program is currently developing technology in three areas that include Propulsion System Technologies, Entry Vehicle Technologies, and Systems Mission Analysis. ISPTs propulsion technologies include: 1) NASAs Evolutionary Xenon Thruster (NEXT) ion propulsion system, a 0.6-7 kW throttle-able gridded ion system; 2) a Hall-effect electric propulsion (HEP) system for sample return and low cost missions; 3) the Advanced Xenon Flow Control System (AXFS); ultra-lightweight propellant tank technologies (ULTT); and propulsion technologies for a Mars Ascent Vehicle (MAV). The AXFS and ULTT are two component technologies being developed with nearer-term flight infusion in mind, whereas NEXT and the HEP are being developed as EP systems. ISPTs entry vehicle technologies are: 1) Aerocapture technology development with investments in a family of thermal protection system (TPS) materials and structures; guidance, navigation, and control (GNC) models of blunt-body rigid aeroshells; and aerothermal effect models; and 2) Multi-mission technologies for Earth Entry Vehicles (MMEEV) for sample return missions. The Systems Mission Analysis area is focused on developing tools and assessing the application of propulsion, entry vehicle, and spacecraft bus technologies to a wide variety of mission concepts. Several of the ISPT technologies are related to sample return missions and other spacecraft bus technology needs like: MAV propulsion, MMEEV, and electric propulsion. These technologies, as well as Aerocapture, are more vehicle and mission-focused, and present a different set of technology development challenges. These in-space propulsion technologies are applicable, and potentially enabling for future NASA Discovery, New Frontiers, Flagship and sample return missions currently under consideration. This paper provides a brief overview of the ISPT program, describing the development status and technology infusion readiness.

A novel technology coupling extraction and foam fractionation for separating the total saponins from Achyranthes bidentata.

PubMed

Ding, Linlin; Wang, Yanji; Wu, Zhaoliang; Liu, Wei; Li, Rui; Wang, Yanyan

2016-10-02

A novel technology coupling extraction and foam fractionation was developed for separating the total saponins from Achyranthes bidentata. In the developed technology, the powder of A. bidentata was loaded in a nylon filter cloth pocket with bore diameter of 180 µm. The pocket was fixed in the bulk liquid phase for continuously releasing saponins. Under the optimal conditions, the concentration and the extraction rate of the total saponins in the foamate by the developed technology were 73.5% and 416.2% higher than those by the traditional technology, respectively. The foamates obtained by the traditional technology and the developed technology were analyzed by ultraperformance liquid chromatography-mass spectrometry to determine their ingredients, and the results appeared that the developed technology exhibited a better performance for separating saponins than the traditional technology. The study is expected to develop a novel technology for cost effectively separating plant-derived materials with surface activity.

NASA Goddard Thermal Technology Overview 2018

NASA Technical Reports Server (NTRS)

Butler, Dan; Swanson, Ted

2018-01-01

This presentation summarizes the current plans and efforts at NASA/Goddard to develop new thermal control technology for anticipated future missions. It will also address some of the programmatic developments currently underway at NASA, especially with respect to the NASA Technology Development Program. The effects of the recently submitted NASA budget will also be addressed. While funding for basic technology development is still tight, significant efforts are being made in direct support of flight programs. Thermal technology Implementation on current flight programs will be reviewed, and the recent push for Cube-sat mission development will also be addressed. Many of these technologies also have broad applicability to DOD, DOE, and commercial programs. Partnerships have been developed with the Air Force, Navy, and various universities to promote technology development. In addition, technology development activities supported by internal research and development (IRAD) program and the Small Business Innovative Research (SBIR) program are reviewed in this presentation. Specific technologies addressed include; two-phase systems applications and issues on NASA missions, latest developments of thermal control coatings, Atomic Layer Deposition (ALD), Micro-scale Heat Transfer, and various other research activities.

Appropriate strategies.

PubMed

Halty, M

1979-01-01

Technology strategies are concerned with the production, distribution, and consumption of technology. Observation of less developed countries (LDCs) and international organizations shows that little attention is given to the development of a technology strategy. LDCs need to formulate a strategy of self-reliant technological development for the next decade. They should no longer be content to stand in a technologically dependent relationship to the developed countries. Such strategies must balance the ratio between investment in indigenous technologies and expenditure for foreign technology. The strategies change according to the level of industrialization achieved. The following considerations come into development of technology strategies: 1) determination of an appropriate balance among the accumulation, consumption, and distribution of technology; 2) the amount and level of government support; and 3) the balance between depth and breadth of technology to be encouraged.

One chip at a time: using technology to enhance youth development.

PubMed

Cohall, Alwyn; Nshom, Montsine; Nye, Andrea

2007-08-01

Youth development programs have the potential to positively impact psychosocial growth and maturation in young adults. Several youth development programs are capitalizing on youths' natural gravitation toward technology as well. Research has shown that youth view technology and technologic literacy as positive and empowering, and that youth who master technology have increased self-esteem and better socioeconomic prospects than their counterparts. Technology-centered youth development programs offer a unique opportunity to engage youth, thereby extending their social networks, enhancing their access to information, building their self-esteem, and improving their self-efficacy. This article provides an overview of the intersection between youth development and technology and illustrates the ways technology can be used as a cutting-edge tool for youth development.

Mirror Technology Development for The International X-Ray Observatory Mission

NASA Technical Reports Server (NTRS)

Zhang, Will

2010-01-01

Presentation slides include: International X-ray Observatory (IXO), Lightweight and High Resolution X-ray Optics is Needed; Modular Design of Mirror Assembly, IXO Mirror Technology Development Objectives, Focus of Technology Development, Slumping - Status, Mirror Fabrication Progress, Temporary Bonding - Status, Alignment - Status, Permanent Bonding - Status, Mirror Housing Simulator (MHS) - TRL-4, Mini-Module (TRL-5), Flight-Like Module (TRL-6), Mirror Technology Development Team, Outlook, and Small Technology Firms that Have Made Direct Contributions to IXO Mirror Technology Development.

Mission oriented R and D and the advancement of technology: The imapct of NASA contributions, volume 1

NASA Technical Reports Server (NTRS)

Robbins, M. D.; Kelley, J. A.; Elliott, L.

1972-01-01

The contributions of NASA to the advancement of major developments in several selected fields of technology are identified. Subjects discussed are: (1) developing new knowledge, (2) developing new technology, (3) demonstrating the application of new technology for the first time, (4) augmenting existing technology, (5) applying existing technology in a new context, (6) stimulating industry to acquire or develop new technology, (7) identifying problem areas requiring further research, and (8) creating new markets.

A summary of the status of biomass conversion technologies and opportunities for their use in developing countries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waddle, D.B.; Perlack, R.D.; Wimberly, J.

1990-01-01

Biomass plays a significant role in energy use in developing countries: however, these resources are often used very inefficiently. Recent technology developments have made possible improved conversion efficiencies for utility scale technologies. These developments may be of interest in the wake of recent policy changes occurring in several developing countries, with respect to independent power production. Efforts are also being directed at developing biomass conversion technologies that can interface and/or compete with internal combustion engines for small, isolated loads. This paper reviews the technological status of biomass conversion technologies appropriate for commercial, industrial, and small utility applications in developing countries.more » Market opportunities, constraints, and technology developments are also discussed. 25 refs., 1 fig., 1 tab.« less

An On-Line Technology Information System (OTIS) for Advanced Life Support

NASA Technical Reports Server (NTRS)

Levri, Julie A.; Boulanger, Richard; Hoganm John A.; Rodriquez, Luis

2003-01-01

An On-line Technology Information System (OTIS) is currently being developed for the Advanced Life Support (ALS) Program. This paper describes the preliminary development of OTIS, which is a system designed to provide centralized collection and organization of technology information. The lack of thorough, reliable and easily understood technology information is a major obstacle in effective assessment of technology development progress, trade studies, metric calculations, and technology selection for integrated testing. OTIS will provide a formalized, well-organized protocol to communicate thorough, accurate, current and relevant technology information between the hands-on technology developer and the ALS Community. The need for this type of information transfer system within the Solid Waste Management (SWM) element was recently identified and addressed. A SWM Technology Information Form (TIF) was developed specifically for collecting detailed technology information in the area of SWM. In the TIF, information is requested from SWM technology developers, based upon the Technology Readiness Level (TRL). Basic information is requested for low-TRL technologies, and more detailed information is requested as the TRL of the technology increases. A comparable form is also being developed for the wastewater processing element. In the future, similar forms will also be developed for the ALS elements of air revitalization, food processing, biomass production and thermal control. These ALS element-specific forms will be implemented in OTIS via a web-accessible interface,with the data stored in an object-oriented relational database (created in MySQLTM) located on a secure server at NASA Ames Research Center. With OTIS, ALS element leads and managers will be able to carry out informed research and development investment, thereby promoting technology through the TRL scale. OTIS will also allow analysts to make accurate evaluations of technology options. Additionally, the range and specificity of information solicited will help educate technology developers of programmatic needs.

Ares Project Technology Assessment: Approach and Tools

NASA Technical Reports Server (NTRS)

Hueter, Uwe; Tyson, Richard

2010-01-01

Technology assessments provide a status of the development maturity of specific technologies. Along with benefit analysis, the risks the project assumes can be quantified. Normally due to budget constraints, the competing technologies are prioritized and decisions are made which ones to fund. A detailed technology development plan is produced for the selected technologies to provide a roadmap to reach the desired maturity by the project s critical design review. Technology assessments can be conducted for both technology only tasks or for product development programs. This paper is primarily biased toward the product development programs. The paper discusses the Ares Project s approach to technology assessment. System benefit analysis, risk assessment, technology prioritization, and technology readiness assessment are addressed. A description of the technology readiness level tool being used is provided.

78 FR 17418 - Rural Health Information Technology Network Development Grant

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-21

... Information Technology Network Development Grant AGENCY: Health Resources and Services Administration (HRSA...-competitive replacement award under the Rural Health Information Technology Network Development Grant (RHITND... relinquishing its fiduciary responsibilities for the Rural Health Information Technology Network Development...

Method for technology-delivered healthcare measures.

PubMed

Kramer-Jackman, Kelli Lee; Popkess-Vawter, Sue

2011-12-01

Current healthcare literature lacks development and evaluation methods for research and practice measures administered by technology. Researchers with varying levels of informatics experience are developing technology-delivered measures because of the numerous advantages they offer. Hasty development of technology-delivered measures can present issues that negatively influence administration and psychometric properties. The Method for Technology-delivered Healthcare Measures is designed to systematically guide the development and evaluation of technology-delivered measures. The five-step Method for Technology-delivered Healthcare Measures includes establishment of content, e-Health literacy, technology delivery, expert usability, and participant usability. Background information and Method for Technology-delivered Healthcare Measures steps are detailed.

Software Engineering Research/Developer Collaborations in 2005

NASA Technical Reports Server (NTRS)

Pressburger, Tom

2006-01-01

In CY 2005, three collaborations between software engineering technology providers and NASA software development personnel deployed three software engineering technologies on NASA development projects (a different technology on each project). The main purposes were to benefit the projects, infuse the technologies if beneficial into NASA, and give feedback to the technology providers to improve the technologies. Each collaboration project produced a final report. Section 2 of this report summarizes each project, drawing from the final reports and communications with the software developers and technology providers. Section 3 indicates paths to further infusion of the technologies into NASA practice. Section 4 summarizes some technology transfer lessons learned. Also included is an acronym list.

Technology for small spacecraft

NASA Technical Reports Server (NTRS)

1994-01-01

This report gives the results of a study by the National Research Council's Panel on Small Spacecraft Technology that reviewed NASA's technology development program for small spacecraft and assessed technology within the U.S. government and industry that is applicable to small spacecraft. The panel found that there is a considerable body of advanced technology currently available for application by NASA and the small spacecraft industry that could provide substantial improvement in capability and cost over those technologies used for current NASA small spacecraft. These technologies are the result of developments by commercial companies, Department of Defense agencies, and to a lesser degree NASA. The panel also found that additional technologies are being developed by these same entities that could provide additional substantial improvement if development is successfully completed. Recommendations for future technology development efforts by NASA across a broad technological spectrum are made.

Sensors 2000! Program: Advanced Biosensor and Measurement Systems Technologies for Spaceflight Research and Concurrent, Earth-Based Applications

NASA Technical Reports Server (NTRS)

Hines, J.

1999-01-01

Sensors 2000! (S2K!) is a specialized, integrated projects team organized to provide focused, directed, advanced biosensor and bioinstrumentation systems technology support to NASA's spaceflight and ground-based research and development programs. Specific technology thrusts include telemetry-based sensor systems, chemical/ biological sensors, medical and physiological sensors, miniaturized instrumentation architectures, and data and signal processing systems. A concurrent objective is to promote the mutual use, application, and transition of developed technology by collaborating in academic-commercial-govemment leveraging, joint research, technology utilization and commercialization, and strategic partnering alliances. Sensors 2000! is organized around three primary program elements: Technology and Product Development, Technology infusion and Applications, and Collaborative Activities. Technology and Product Development involves development and demonstration of biosensor and biotelemetry systems for application to NASA Space Life Sciences Programs; production of fully certified spaceflight hardware and payload elements; and sensor/measurement systems development for NASA research and development activities. Technology Infusion and Applications provides technology and program agent support to identify available and applicable technologies from multiple sources for insertion into NASA's strategic enterprises and initiatives. Collaborative Activities involve leveraging of NASA technologies with those of other government agencies, academia, and industry to concurrently provide technology solutions and products of mutual benefit to participating members.

IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia.

PubMed

Kuett, Alexander; Rieger, Christina; Perathoner, Deborah; Herold, Tobias; Wagner, Michaela; Sironi, Silvia; Sotlar, Karl; Horny, Hans-Peter; Deniffel, Christian; Drolle, Heidrun; Fiegl, Michael

2015-12-17

The bone marrow microenvironment is physiologically hypoxic with areas being as low as 1% O2, e.g. the stem cell niche. Acute myeloid leukaemia (AML) blasts misuse these bone marrow niches for protection by the local microenvironment, but also might create their own microenvironment. Here we identify IL-8 as a hypoxia-regulated cytokine in both AML cell lines and primary AML samples that is induced within 48 hours of severe hypoxia (1% O2). IL-8 lacked effects on AML cells but induced migration in mesenchymal stromal cells (MSC), an integral part of the bone marrow. Accordingly, MSC were significantly increased in AML bone marrow as compared to healthy bone marrow. Interestingly, mononuclear cells obtained from healthy bone marrow displayed both significantly lower endogenous and hypoxia-induced production of IL-8. IL-8 mRNA expression in AML blasts from 533 patients differed between genetic subgroups with significantly lower expression of IL-8 in acute promyelocytic leukaemia (APL), while in non APL-AML patients with FLT ITD had the highest IL-8 expression. In this subgroup, high IL-8 expression was also prognostically unfavourable. In conclusion, hypoxia as encountered in the bone marrow specifically increases IL-8 expression of AML, which in turn impacts niche formation. High IL-8 expression might be correlated with poor prognosis in certain AML subsets.

Outcome of children with high-risk acute myeloid leukemia given autologous or allogeneic hematopoietic cell transplantation in the aieop AML-2002/01 study.

PubMed

Locatelli, F; Masetti, R; Rondelli, R; Zecca, M; Fagioli, F; Rovelli, A; Messina, C; Lanino, E; Bertaina, A; Favre, C; Giorgiani, G; Ripaldi, M; Ziino, O; Palumbo, G; Pillon, M; Pession, A; Rutella, S; Prete, A

2015-02-01

We analyzed the outcome of 243 children with high-risk (HR) AML in first CR1 enrolled in the AIEOP-2002/01 protocol, who were given either allogeneic (ALLO; n=141) or autologous (AUTO; n=102) hematopoietic SCT (HSCT), depending on the availability of a HLA-compatible sibling. Infants, patients with AML-M7, or complex karyotype or those with FLT3-ITD, were eligible to be transplanted also from alternative donors. All patients received a myeloablative regimen combining busulfan, cyclophosphamide and melphalan; [corrected] AUTO-HSCT patients received BM cells in most cases, while in children given ALLO-HSCT stem cell source was BM in 96, peripheral blood in 19 and cord blood in 26. With a median follow-up of 57 months (range 12-130), the probability of disease-free survival (DFS) was 73% and 63% in patients given either ALLO- or AUTO-HSCT, respectively (P=NS). Although the cumulative incidence (CI) of relapse was lower in ALLO- than in AUTO-HSCT recipients (17% vs 28%, respectively; P=0.043), the CI of TRM was 7% in both groups. Patients transplanted with unrelated donor cord blood had a remarkable 92.3% 8-year DFS probability. Altogether, these data confirm that HSCT is a suitable option for preventing leukemia recurrence in HR children with CR1 AML.

Enhanced Vertical Perception through Head-Related Impulse Response Customization Based on Pinna Response Tuning in the Median Plane

NASA Astrophysics Data System (ADS)

Shin, Ki Hoon; Park, Youngjin

Human's ability to perceive elevation of a sound and distinguish whether a sound is coming from the front or rear strongly depends on the monaural spectral features of the pinnae. In order to realize an effective virtual auditory display by HRTF (head-related transfer function) customization, the pinna responses were isolated from the median HRIRs (head-related impulse responses) of 45 individual HRIRs in the CIPIC HRTF database and modeled as linear combinations of 4 or 5 basic temporal shapes (basis functions) per each elevation on the median plane by PCA (principal components analysis) in the time domain. By tuning the weight of each basis function computed for a specific height to replace the pinna response in the KEMAR HRIR at the same height with the resulting customized pinna response and listening to the filtered stimuli over headphones, 4 individuals with normal hearing sensitivity were able to create a set of HRIRs that outperformed the KEMAR HRIRs in producing vertical effects with reduced front/back ambiguity in the median plane. Since the monaural spectral features of the pinnae are almost independent of azimuthal variation of the source direction, similar vertical effects could also be generated at different azimuthal directions simply by varying the ITD (interaural time difference) according to the direction as well as the size of each individual's own head.

Evaluation of an impedance threshold device in patients receiving active compression-decompression cardiopulmonary resuscitation for out of hospital cardiac arrest.

PubMed

Plaisance, Patrick; Lurie, Keith G; Vicaut, Eric; Martin, Dominique; Gueugniaud, Pierre-Yves; Petit, Jean-Luc; Payen, Didier

2004-06-01

The purpose of this multicentre clinical randomized controlled blinded prospective trial was to determine whether an inspiratory impedance threshold device (ITD), when used in combination with active compression-decompression (ACD) cardiopulmonary resuscitation (CPR), would improve survival rates in patients with out-of-hospital cardiac arrest. Patients were randomized to receive either a sham (n = 200) or an active impedance threshold device (n = 200) during advanced cardiac life support performed with active compression-decompression cardiopulmonary resuscitation. The primary endpoint of this study was 24 h survival. The 24 h survival rates were 44/200 (22%) with the sham valve and 64/200 (32%) with the active valve (P = 0.02). The number of patients who had a return of spontaneous circulation (ROSC), intensive care unit (ICU) admission, and hospital discharge rates was 77 (39%), 57 (29%), and 8 (4%) in the sham valve group versus 96 (48%) (P = 0.05), 79 (40%) (P = 0.02), and 10 (5%) (P = 0.6) in the active valve group. Six out of ten survivors in the active valve group and 1/8 survivors in the sham group had normal neurological function at hospital discharge (P = 0.1). The use of an impedance valve in patients receiving active compression-decompression cardiopulmonary resuscitation for out-of-hospital cardiac arrest significantly improved 24 h survival rates.

Full-length mutation search of the TP53 gene in acute myeloid leukemia has increased significance as a prognostic factor.

PubMed

Terada, Kazuki; Yamaguchi, Hiroki; Ueki, Toshimitsu; Usuki, Kensuke; Kobayashi, Yutaka; Tajika, Kenji; Gomi, Seiji; Kurosawa, Saiko; Miyadera, Keiki; Tokura, Taichiro; Omori, Ikuko; Marumo, Atushi; Fujiwara, Yusuke; Yui, Shunsuke; Ryotokuji, Takeshi; Osaki, Yoshiki; Arai, Kunihito; Kitano, Tomoaki; Kosaka, Fumiko; Wakita, Satoshi; Tamai, Hayato; Fukuda, Takahiro; Inokuchi, Koiti

2018-01-01

TP53 gene abnormality has been reported to be an unfavorable prognostic factor in acute myeloid leukemia (AML). However, almost all studies of TP53 gene abnormality so far have been limited to mutation searches in the DNA binding domain. As there have been few reports examining both mutation and deletion over the full-length of the TP53 gene, the clinical characteristics of TP53 gene abnormality have not yet been clearly established. In this study, TP53 gene mutation was observed in 7.3% of the total 412 de novo AML cases (33 mutations in 30 cases), with mutation outside the DNA binding domain in eight cases (27%). TP53 gene deletion was observed in 3.1% of 358 cases. All cases had monoallelic deletion with TP53 gene mutation on the opposite allele. Multivariate analysis demonstrated that TP53 gene mutation in the DNA binding domain and outside the DNA binding domain was an independent poor prognostic factor for overall survival and relapse-free survival among the total cohort and it is also an unfavorable prognostic factor in FLT3-ITD-negative AML cases aged 70 years or below with intermediate cytogenetic prognosis. In stratified treatment, full-length search for TP53 gene mutation is therefore very important.

Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study.

PubMed

Thomas, Xavier; Elhamri, Mohamed; Raffoux, Emmanuel; Renneville, Aline; Pautas, Cécile; de Botton, Stéphane; de Revel, Thierry; Reman, Oumedaly; Terré, Christine; Gardin, Claude; Chelghoum, Youcef; Boissel, Nicolas; Quesnel, Bruno; Hicheri, Yosr; Bourhis, Jean-Henri; Fenaux, Pierre; Preudhomme, Claude; Michallet, Mauricette; Castaigne, Sylvie; Dombret, Hervé

2011-08-18

To assess the value of administering timed-sequential chemotherapy (TSC; 2 therapeutic sequences separated by a 4-day interval-free chemotherapy) or high-dose cytarabine (HDAraC) cycles in consolidation therapy for acute myeloid leukemia (AML), 459 patients 15 to 50 years of age were enrolled in the prospective randomized Acute Leukemia French Association-9802 trial. Complete remission was achieved in 89%. A total of 237 patients were then randomized to either TSC consolidation (120 patients) or HDAraC consolidation cycles (117 patients). Overall, there was no significant difference between the 2 consolidation arms (5-year event-free survival [EFS]: 41% for HDAraC vs 35% for TSC), or cumulative incidence of relapse, or treatment-related mortality. Cytogenetically normal AML NPM1(+) or CEBPA(+) and FLT3-ITD(-) had the same outcome as those with favorable cytogenetics. When considering favorable and unfavorable risk groups, the trend was in favor of HDAraC. However, the difference became significant when considering intermediate cytogenetics (5-year EFS: 49% vs 29%; P = .02), especially cytogenetically normal AML (5-year EFS: 48% vs 31%; P = .04), which was related to lower relapse rate and less toxicity. This study demonstrates that TSC did not produce any benefit when used as consolidation therapy in younger adults compared with HDAraC. This trial was registered at www.clinicaltrials.gov as #NCT00880243.

Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia.

PubMed

Jourdan, Eric; Boissel, Nicolas; Chevret, Sylvie; Delabesse, Eric; Renneville, Aline; Cornillet, Pascale; Blanchet, Odile; Cayuela, Jean-Michel; Recher, Christian; Raffoux, Emmanuel; Delaunay, Jacques; Pigneux, Arnaud; Bulabois, Claude-Eric; Berthon, Céline; Pautas, Cécile; Vey, Norbert; Lioure, Bruno; Thomas, Xavier; Luquet, Isabelle; Terré, Christine; Guardiola, Philippe; Béné, Marie C; Preudhomme, Claude; Ifrah, Norbert; Dombret, Hervé

2013-03-21

Not all patients with core binding factor acute myeloid leukemia (CBF-AML) display a good outcome. Modern risk factors include KIT and/or FLT3 gene mutations and minimal residual disease (MRD) levels, but their respective values have never been prospectively assessed. A total of 198 CBF-AML patients were randomized between a reinforced and a standard induction course, followed by 3 high-dose cytarabine consolidation courses. MRD levels were monitored prospectively. Gene mutations were screened at diagnosis. Despite a more rapid MRD decrease after reinforced induction, induction arm did not influence relapse-free survival (RFS) (64% in both arms; P = .91). Higher WBC, KIT, and/or FLT3-ITD/TKD gene mutations, and a less than 3-log MRD reduction after first consolidation, were associated with a higher specific hazard of relapse, but MRD remained the sole prognostic factor in multivariate analysis. At 36 months, cumulative incidence of relapse and RFS were 22% vs 54% (P < .001) and 73% vs 44% (P < .001) in patients who achieved 3-log MRD reduction vs the others. These results suggest that MRD, rather than gene mutations, should be used for future treatment stratifications in CBF-AML patients. This trial was registered at EudraCT as #2006-005163-26 and at www.clinicaltrials.gov as #NCT 00428558.

Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells

PubMed Central

Kunimoto, Hiroyoshi; McKenney, Anna Sophia; Meydan, Cem; Shank, Kaitlyn; Nazir, Abbas; Rapaport, Franck; Durham, Benjamin; Garrett-Bakelman, Francine E.; Pronier, Elodie; Shih, Alan H.; Melnick, Ari; Chaudhuri, Jayanta

2017-01-01

Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic-specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating TET2 as a master regulator of normal and malignant hematopoiesis. Despite the functional link between AID and TET in epigenetic gene regulation, the role of AID loss in hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and reduced erythroid progenitors resulting in anemia, with dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage-specific transcription factors. Consistent with data in the murine context, silencing of AID in human bone marrow cells skews differentiation toward myelomonocytic lineage. However, in contrast to Tet2 loss, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD to induce myeloid transformation. Genome-wide transcription and differential methylation analysis uncover the critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, however, their role is nonredundant in regulating HSC self-renewal and in myeloid transformation. PMID:28077417

Using ILD or ITD Cues for Sound Source Localization and Speech Understanding in a Complex Listening Environment by Listeners With Bilateral and With Hearing-Preservation Cochlear Implants.

PubMed

Loiselle, Louise H; Dorman, Michael F; Yost, William A; Cook, Sarah J; Gifford, Rene H

2016-08-01

To assess the role of interaural time differences and interaural level differences in (a) sound-source localization, and (b) speech understanding in a cocktail party listening environment for listeners with bilateral cochlear implants (CIs) and for listeners with hearing-preservation CIs. Eleven bilateral listeners with MED-EL (Durham, NC) CIs and 8 listeners with hearing-preservation CIs with symmetrical low frequency, acoustic hearing using the MED-EL or Cochlear device were evaluated using 2 tests designed to task binaural hearing, localization, and a simulated cocktail party. Access to interaural cues for localization was constrained by the use of low-pass, high-pass, and wideband noise stimuli. Sound-source localization accuracy for listeners with bilateral CIs in response to the high-pass noise stimulus and sound-source localization accuracy for the listeners with hearing-preservation CIs in response to the low-pass noise stimulus did not differ significantly. Speech understanding in a cocktail party listening environment improved for all listeners when interaural cues, either interaural time difference or interaural level difference, were available. The findings of the current study indicate that similar degrees of benefit to sound-source localization and speech understanding in complex listening environments are possible with 2 very different rehabilitation strategies: the provision of bilateral CIs and the preservation of hearing.

MicroRNA expression at diagnosis adds relevant prognostic information to molecular categorization in patients with intermediate-risk cytogenetic acute myeloid leukemia.

PubMed

Díaz-Beyá, M; Brunet, S; Nomdedéu, J; Tejero, R; Díaz, T; Pratcorona, M; Tormo, M; Ribera, J M; Escoda, L; Duarte, R; Gallardo, D; Heras, I; Queipo de Llano, M P; Bargay, J; Monzo, M; Sierra, J; Navarro, A; Esteve, J

2014-04-01

Acute myeloid leukemia (AML) is a heterogeneous disease, and optimal treatment varies according to cytogenetic risk factors and molecular markers. Several studies have demonstrated the prognostic importance of microRNAs (miRNAs) in AML. Here we report a potential association between miRNA expression and clinical outcome in 238 intermediate-risk cytogenetic AML (IR-AML) patients from 16 institutions in the CETLAM cooperative group. We first profiled 670 miRNAs in a subset of 85 IR-AML patients from a single institution and identified 10 outcome-related miRNAs. We then validated these 10 miRNAs by individual assays in the total cohort and confirmed the prognostic impact of 4 miRNAs. High levels of miR-196b and miR-644 were independently associated with shorter overall survival, and low levels of miR-135a and miR-409-3p with a higher risk of relapse. Interestingly, miR-135a and miR-409-3p maintained their independent prognostic value within the unfavorable molecular subcategory (wild-type NPM1 and CEBPA and/or FLT3-ITD), and miR-644 retained its value within the favorable molecular subcategory. miR-409-3p, miR-135a, miR-196b and mir-644 arose as prognostic markers for IR-AML, both overall and within specific molecular subgroups.

The Status of Spacecraft Bus and Platform Technology Development under the NASA ISPT Program

NASA Technical Reports Server (NTRS)

Anderson, David J.; Munk, Michelle M.; Pencil, Eric; Dankanich, John; Glaab, Louis; Peterson, Todd

2013-01-01

The In-Space Propulsion Technology (ISPT) program is developing spacecraft bus and platform technologies that will enable or enhance NASA robotic science missions. The ISPT program is currently developing technology in four areas that include Propulsion System Technologies (electric and chemical), Entry Vehicle Technologies (aerocapture and Earth entry vehicles), Spacecraft Bus and Sample Return Propulsion Technologies (components and ascent vehicles), and Systems/Mission Analysis. Three technologies are ready for near-term flight infusion: 1) the high-temperature Advanced Material Bipropellant Rocket (AMBR) engine providing higher performance; 2) NASA s Evolutionary Xenon Thruster (NEXT) ion propulsion system, a 0.6-7 kW throttle-able gridded ion system; and 3) Aerocapture technology development with investments in a family of thermal protection system (TPS) materials and structures; guidance, navigation, and control (GN&C) models of blunt-body rigid aeroshells; and aerothermal effect models. Two component technologies being developed with flight infusion in mind are the Advanced Xenon Flow Control System and ultralightweight propellant tank technologies. Future directions for ISPT are technologies that relate to sample return missions and other spacecraft bus technology needs like: 1) Mars Ascent Vehicles (MAV); 2) multi-mission technologies for Earth Entry Vehicles (MMEEV); and 3) electric propulsion. These technologies are more vehicles and mission-focused, and present a different set of technology development and infusion steps beyond those previously implemented. The Systems/Mission Analysis area is focused on developing tools and assessing the application of propulsion and spacecraft bus technologies to a wide variety of mission concepts. These inspace propulsion technologies are applicable, and potentially enabling for future NASA Discovery, New Frontiers, and sample return missions currently under consideration, as well as having broad applicability to potential Flagship missions. This paper provides a brief overview of the ISPT program, describing the development status and technology infusion readiness of in-space propulsion technologies in the areas of electric propulsion, Aerocapture, Earth entry vehicles, propulsion components, Mars ascent vehicle, and mission/systems analysis.

The status of spacecraft bus and platform technology development under the NASA ISPT program

NASA Astrophysics Data System (ADS)

Anderson, D. J.; Munk, M. M.; Pencil, E.; Dankanich, J.; Glaab, L.; Peterson, T.

The In-Space Propulsion Technology (ISPT) program is developing spacecraft bus and platform technologies that will enable or enhance NASA robotic science missions. The ISPT program is currently developing technology in four areas that include Propulsion System Technologies (electric and chemical), Entry Vehicle Technologies (aerocapture and Earth entry vehicles), Spacecraft Bus and Sample Return Propulsion Technologies (components and ascent vehicles), and Systems/Mission Analysis. Three technologies are ready for near-term flight infusion: 1) the high-temperature Advanced Material Bipropellant Rocket (AMBR) engine providing higher performance; 2) NASA's Evolutionary Xenon Thruster (NEXT) ion propulsion system, a 0.6-7 kW throttle-able gridded ion system; and 3) Aerocapture technology development with investments in a family of thermal protection system (TPS) materials and structures; guidance, navigation, and control (GN& C) models of blunt-body rigid aeroshells; and aerothermal effect models. Two component technologies being developed with flight infusion in mind are the Advanced Xenon Flow Control System and ultra-lightweight propellant tank technologies. Future directions for ISPT are technologies that relate to sample return missions and other spacecraft bus technology needs like: 1) Mars Ascent Vehicles (MAV); 2) multi-mission technologies for Earth Entry Vehicles (MMEEV); and 3) electric propulsion. These technologies are more vehicles and mission-focused, and present a different set of technology development and infusion steps beyond those previously implemented. The Systems/Mission Analysis area is focused on developing tools and assessing the application of propulsion and spacecraft bus technologies to a wide variety of mission concepts. These in-space propulsion technologies are applicable, and potentially enabling for future NASA Discovery, New Frontiers, and sample return missions currently under consideration, as well as having broad applicabilit- to potential Flagship missions. This paper provides a brief overview of the ISPT program, describing the development status and technology infusion readiness of in-space propulsion technologies in the areas of electric propulsion, Aerocapture, Earth entry vehicles, propulsion components, Mars ascent vehicle, and mission/systems analysis.

The Status of Spacecraft Bus and Platform Technology Development Under the NASA ISPT Program

NASA Technical Reports Server (NTRS)

Anderson, David J.; Munk, Michelle M.; Pencil, Eric J.; Dankanich, John; Glaab, Louis J.

2013-01-01

The In-Space Propulsion Technology (ISPT) program is developing spacecraft bus and platform technologies that will enable or enhance NASA robotic science missions. The ISPT program is currently developing technology in four areas that include Propulsion System Technologies (electric and chemical), Entry Vehicle Technologies (aerocapture and Earth entry vehicles), Spacecraft Bus and Sample Return Propulsion Technologies (components and ascent vehicles), and Systems/Mission Analysis. Three technologies are ready for near-term flight infusion: 1) the high-temperature Advanced Material Bipropellant Rocket (AMBR) engine providing higher performance 2) NASAs Evolutionary Xenon Thruster (NEXT) ion propulsion system, a 0.6-7 kW throttle-able gridded ion system and 3) Aerocapture technology development with investments in a family of thermal protection system (TPS) materials and structures guidance, navigation, and control (GN&C) models of blunt-body rigid aeroshells and aerothermal effect models. Two component technologies being developed with flight infusion in mind are the Advanced Xenon Flow Control System, and ultra-lightweight propellant tank technologies. Future direction for ISPT are technologies that relate to sample return missions and other spacecraft bus technology needs like: 1) Mars Ascent Vehicles (MAV) 2) multi-mission technologies for Earth Entry Vehicles (MMEEV) and 3) electric propulsion. These technologies are more vehicle and mission-focused, and present a different set of technology development and infusion steps beyond those previously implemented. The Systems/Mission Analysis area is focused on developing tools and assessing the application of propulsion and spacecraft bus technologies to a wide variety of mission concepts. These in-space propulsion technologies are applicable, and potentially enabling for future NASA Discovery, New Frontiers, and sample return missions currently under consideration, as well as having broad applicability to potential Flagship missions. This paper provides a brief overview of the ISPT program, describing the development status and technology infusion readiness of in-space propulsion technologies in the areas of electric propulsion, Aerocapture, Earth entry vehicles, propulsion components, Mars ascent vehicle, and mission/systems analysis.

NASA Goddard Thermal Technology Overview 2017

NASA Technical Reports Server (NTRS)

Butler, Dan; Swanson, Ted

2017-01-01

This presentation summarizes the current plans and efforts at NASA Goddard to develop new thermal control technology for anticipated future missions. It will also address some of the programmatic developments currently underway at NASA, especially with respect to the NASA Technology Development Program. The effects of the recently enacted FY 17 NASA budget, which includes a sizeable increase, will also be addressed. While funding for basic technology development is still tight, significant efforts are being made in direct support of flight programs. Thermal technology Implementation on current flight programs will be reviewed, and the recent push for CubeSat mission development will also be addressed. Many of these technologies also have broad applicability to DOD (Dept. of Defense), DOE (Dept. of the Environment), and commercial programs. Partnerships have been developed with the Air Force, Navy, and various universities to promote technology development. In addition, technology development activities supported by internal research and development (IRAD) program and the Small Business Innovative Research (SBIR) program are reviewed in this presentation. Specific technologies addressed include; two-phase systems applications and issues on NASA missions, latest developments of electro-hydrodynamically pumped systems, Atomic Layer Deposition (ALD), Micro-scale Heat Transfer, and various other research activities.

NASA Goddard Thermal Technology Overview 2016

NASA Technical Reports Server (NTRS)

Butler, Dan; Swanson, Ted

2016-01-01

This presentation summarizes the current plans and efforts at NASA Goddard to develop new thermal control technology for anticipated future missions. It will also address some of the programmatic developments currently underway at NASA, especially with respect to the NASA Technology Development Program. The effects of the recently enacted FY 16 NASA budget, which includes a sizeable increase, will also be addressed. While funding for basic technology development is still tight, significant efforts are being made in direct support of flight programs. Thermal technology implementation on current flight programs will be reviewed, and the recent push for Cube-sat mission development will also be addressed. Many of these technologies also have broad applicability to DOD, DOE, and commercial programs. Partnerships have been developed with the Air Force, Navy, and various universities to promote technology development. In addition, technology development activities supported by internal research and development (IRAD) program and the Small Business Innovative Research (SBIR) program are reviewed in this presentation. Specific technologies addressed include; two-phase systems applications and issues on NASA missions, latest developments of electro-hydrodynamically pumped systems, Atomic Layer Deposition (ALD), Micro-scale Heat Transfer, and various other research activities.

Research on robotics by principal investigators of the Robotics Technology Development Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harrigan, R.W.

The U.S. Department of Energy`s Office of Technology Development has been developing robotics and automation technologies for the clean-up and handling of hazardous and radioactive waste through one of its major elements, Cross Cutting and Advanced Technology development. CC&AT university research and development programs recognize the strong technology, base resident in the university community and sponsor a focused technology research and development program which stresses close interaction between the university sector and the DOE community. This report contains a compilation of research articles by each of 14 principle investigators supported by CC&AT to develop robotics and automation technologies for themore » clean-up and handling of hazardous and radioactive waste. This research has led to innovative solutions for waste clean-up problems, and it has moved technology out of university laboratories into functioning systems which has allowed early evaluation by site technologists.« less

Policy issues inherent in advanced technology development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baumann, P.D.

1994-12-31

In the development of advanced technologies, there are several forces which are involved in the success of the development of those technologies. In the overall development of new technologies, a sufficient number of these forces must be present and working in order to have a successful opportunity at developing, introducing and integrating into the marketplace a new technology. This paper discusses some of these forces and how they enter into the equation for success in advanced technology research, development, demonstration, commercialization and deployment. This paper limits itself to programs which are generally governmental funded, which in essence represent most ofmore » the technology development efforts that provide defense, energy and environmental technological products. Along with the identification of these forces are some suggestions as to how changes may be brought about to better ensure success in a long term to attempt to minimize time and financial losses.« less

Strategy for the Eighties: High Technology Industrial Development.

ERIC Educational Resources Information Center

Kansas State Dept. of Economic Development, Topeka.

The need for high technology development in Kansas is assessed, with attention to community considerations and the roles of universities and state government in fostering technology development and community considerations. After defining a high technology industry, technologically innovative industries are identified, and influences on the…

75 FR 55360 - Networking and Information Technology Research and Development (NITRD) Program: Draft NITRD 2010...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-10

... NATIONAL SCIENCE FOUNDATION Networking and Information Technology Research and Development (NITRD... Information Technology Research and Development (NITRD). ACTION: Notice, request for public comment. FOR..., the National Coordination Office for Networking and Information Technology Research and Development...

Advanced Refrigerator/Freezer Technology Development. Technology Assessment

NASA Technical Reports Server (NTRS)

Gaseor, Thomas; Hunter, Rick; Hamill, Doris

1996-01-01

The NASA Lewis Research Center, through contract with Oceaneering Space Systems, is engaged in a project to develop advanced refrigerator/freezer (R/F) technologies for future Life and Biomedical Sciences space flight missions. The first phase of this project, a technology assessment, has been completed to identify the advanced R/F technologies needed and best suited to meet the requirements for the five R/F classifications specified by Life and Biomedical Science researchers. Additional objectives of the technology assessment were to rank those technologies based on benefit and risk, and to recommend technology development activities that can be accomplished within this project. This report presents the basis, the methodology, and results of the R/F technology assessment, along with technology development recommendations.

The development and technology transfer of software engineering technology at NASA. Johnson Space Center

NASA Technical Reports Server (NTRS)

Pitman, C. L.; Erb, D. M.; Izygon, M. E.; Fridge, E. M., III; Roush, G. B.; Braley, D. M.; Savely, R. T.

1992-01-01

The United State's big space projects of the next decades, such as Space Station and the Human Exploration Initiative, will need the development of many millions of lines of mission critical software. NASA-Johnson (JSC) is identifying and developing some of the Computer Aided Software Engineering (CASE) technology that NASA will need to build these future software systems. The goal is to improve the quality and the productivity of large software development projects. New trends are outlined in CASE technology and how the Software Technology Branch (STB) at JSC is endeavoring to provide some of these CASE solutions for NASA is described. Key software technology components include knowledge-based systems, software reusability, user interface technology, reengineering environments, management systems for the software development process, software cost models, repository technology, and open, integrated CASE environment frameworks. The paper presents the status and long-term expectations for CASE products. The STB's Reengineering Application Project (REAP), Advanced Software Development Workstation (ASDW) project, and software development cost model (COSTMODL) project are then discussed. Some of the general difficulties of technology transfer are introduced, and a process developed by STB for CASE technology insertion is described.

Cutting Edge Technologies Presentation: An Overview of Developing Sensor Technology Directions and Possible Barriers to New Technology Implementation

NASA Technical Reports Server (NTRS)

Hunter, Gary W.

2007-01-01

The aerospace industry requires the development of a range of chemical sensor technologies for such applications as leak detection, emission monitoring, fuel leak detection, environmental monitoring, and fire detection. A range of chemical sensors are being developed based on micromachining and microfabrication technology to fabricate microsensors with minimal size, weight, and power consumption; and the use of nanomaterials and structures to develop sensors with improved stability combined with higher sensitivity, However, individual sensors are limited in the amount of information that they can provide in environments that contain multiple chemical species. Thus, sensor arrays are being developed to address detection needs in such multi-species environments. These technologies and technical approaches have direct relevance to breath monitoring for clinical applications. This presentation gives an overview of developing cutting-edge sensor technology and possible barriers to new technology implementation. This includes lessons learned from previous microsensor development, recent work in development of a breath monitoring system, and future directions in the implementation of cutting edge sensor technology.

NASA Development of Aerocapture Technologies

NASA Technical Reports Server (NTRS)

James, Bonnie; Munk, Michelle; Moon, Steve

2003-01-01

Aeroassist technology development is a vital part of the NASA ln-Space Propulsion Program (ISP), which is managed by the NASA Headquarters Office of Space Science, and implemented by the Marshall Space Flight Center in Huntsville, Alabama. Aeroassist is the general term given to various techniques to maneuver a space vehicle within an atmosphere, using aerodynamic forces in lieu of propulsive fuel. Within the ISP, the current aeroassist technology development focus is aerocapture. The objective of the ISP Aerocapture Technology Project (ATP) is to develop technologies that can enable and/or benefit NASA science missions by significantly reducing cost, mass, and/or travel times. To accomplish this objective, the ATP identifies and prioritizes the most promising technologies using systems analysis, technology advancement and peer review, coupled with NASA Headquarters Office of Space Science target requirements. Plans are focused on developing mid-Technology Readiness Level (TRL) technologies to TRL 6 (ready for technology demonstration in space).

NASA Development of Aerocapture Technologies

NASA Technical Reports Server (NTRS)

James, Bonnie; Munk, Michelle; Moon, Steve

2004-01-01

Aeroassist technology development is a vital part of the NASA In-Space Propulsion Program (ISP), which is managed by the NASA Headquarters Office of Space Science, and implemented by the Marshall Space Flight Center in Huntsville, Alabama. Aeroassist is the general term given to various techniques to maneuver a space vehicle within an atmosphere, using aerodynamic forces in lieu of propulsive fuel. Within the ISP, the current aeroassist technology development focus is aerocapture. The objective of the ISP Aerocapture Technology Project (ATP) is to develop technologies that can enable and/or benefit NASA science missions by significantly reducing cost, mass, and/or travel times. To accomplish this objective, the ATP identifies and prioritizes the most promising technologies using systems analysis, technology advancement and peer review, coupled with NASA Headquarters Office of Space Science target requirements. Plans are focused on developing mid-Technology Readiness Level (TRL) technologies to TRL 6 (ready for technology demonstration in space).

Methodologies for Optimum Capital Expenditure Decisions for New Medical Technology

PubMed Central

Landau, Thomas P.; Ledley, Robert S.

1980-01-01

This study deals with the development of a theory and an analytical model to support decisions regarding capital expenditures for complex new medical technology. Formal methodologies and quantitative techniques developed by applied mathematicians and management scientists can be used by health planners to develop cost-effective plans for the utilization of medical technology on a community or region-wide basis. In order to maximize the usefulness of the model, it was developed and tested against multiple technologies. The types of technologies studied include capital and labor-intensive technologies, technologies whose utilization rates vary with hospital occupancy rate, technologies whose use can be scheduled, and limited-use and large-use technologies.

A summary of the status of biomass conversion technologies and opportunities for their use in Latin America

NASA Astrophysics Data System (ADS)

Waddle, D. B.; Perlack, R. D.

1990-03-01

Biomass plays a significant role in energy use in developing countries; however, these resources are often used very inefficiently. Recent technology developments have made possible improved conversion efficiencies for utility scale technologies. These developments may be of interest in the wake of recent policy changes occurring in Central America, with respect to independent power production. Efforts are also being directed at developing biomass conversion technologies that can interface and/or compete with internal combustion engines for small, isolated loads. This paper reviews the technological status of biomass conversion technologies appropriate for commercial, industrial, and small utility applications in developing countries, and in Latin America in particular. Market opportunities, constraints, and technology developments are also discussed.

Technology Alignment and Portfolio Prioritization (TAPP)

NASA Technical Reports Server (NTRS)

Funaro, Gregory V.; Alexander, Reginald A.

2015-01-01

Technology Alignment and Portfolio Prioritization (TAPP) is a method being developed by the Advanced Concepts Office, at NASA Marshall Space Flight Center. The TAPP method expands on current technology assessment methods by incorporating the technological structure underlying technology development, e.g., organizational structures and resources, institutional policy and strategy, and the factors that motivate technological change. This paper discusses the methods ACO is currently developing to better perform technology assessments while taking into consideration Strategic Alignment, Technology Forecasting, and Long Term Planning.

Technology Education Professional Enhancement Project

NASA Technical Reports Server (NTRS)

Hughes, Thomas A., Jr.

1996-01-01

The two goals of this project are: the use of integrative field of aerospace technology to enhance the content and instruction delivered by math, science, and technology teachers through the development of a new publication entitled NASA Technology Today, and to develop a rationale and structure for the study of technology, which establishes the foundation for developing technology education standards and programs of the future.

Space transfer vehicle concepts and requirements study. Volume 2, book 4: Integrated advanced technology development

NASA Technical Reports Server (NTRS)

Weber, Gary A.

1991-01-01

The Space Transfer Vehicle (STV) program provides both an opportunity and a requirement to increase our upper stage capabilities with the development and applications of new technologies. Issues such as man rating, space basing, reusability, and long lunar surface storage times drive the need for new technology developments and applications. In addition, satisfaction of mission requirements such as lunar cargo delivery capability and lunar landing either require new technology development or can be achieved in a more cost-effective manner with judicious applications of advanced technology. During the STV study, advanced technology development requirements and plans have been addressed by the Technology/Advanced Development Working Group composed of NASA and contractor representatives. This report discusses the results to date of this working group. The first section gives an overview of the technologies that have potential or required applications for the STV and identifies those technologies baselined for the STV. Figures are provided that list the technology categories and show the priority placed on those technology categories for either the space-based or ground-based options. The second section covers the plans and schedules for incorporating the technologies into the STV program.

Lunar Surface Systems Supportability Technology Development Roadmap

NASA Technical Reports Server (NTRS)

Oeftering, Richard C.; Struk, Peter M.; Green, Jennifer L.; Chau, Savio N.; Curell, Philip C.; Dempsey, Cathy A.; Patterson, Linda P.; Robbins, William; Steele, Michael A.; DAnnunzio, Anthony;

Johnson Space Center Research and Technology Report

NASA Technical Reports Server (NTRS)

Pido, Kelle; Davis, Henry L. (Technical Monitor)

1999-01-01

As the principle center for NASA's Human Exploration and Development of Space (HEDS) Enterprise, the Johnson Space Center (JSC) leads NASA's development of human spacecraft, human support systems, and human spacecraft operations. To implement this mission, JSC has focused on developing the infrastructure and partnerships that enable the technology development for future NASA programs. In our efforts to develop key technologies, we have found that collaborative relationships with private industry and academia strengthen our capabilities, infuse innovative ideas, and provide alternative applications for our development projects. The American public has entrusted NASA with the responsibility for space--technology development, and JSC is committed to the transfer of the technologies that we develop to the private sector for further development and application. It is our belief that commercialization of NASA technologies benefits both American industry and NASA through technology innovation and continued partnering. To this end, we present the 1998-1999 JSC Research and Technology Report. As your guide to the current JSC technologies, this report showcases the projects in work at JSC that may be of interest to U.S. industry, academia, and other government agencies (federal, state, and local). For each project, potential alternative uses and commercial applications are described.

DEVELOPMENT OF EMERGING TECHNOLOGIES WITHIN THE SITE PROGRAM

EPA Science Inventory

The Site Program is formed by five research programs: the Demonstration Program, the Emerging Technology Program, the Measurement and Monitoring Technology Development Program, the Innovative Technology Program, and the Technology Transfer Program. The Emerging Technology (ET) P...

Developing a Strategic Plan for NASA JSC's Technology Investments

NASA Technical Reports Server (NTRS)

Stecklein, Jonette M.

2012-01-01

Human space exploration has always been heavily influenced by goals to achieve a specific mission on a specific schedule. This approach drove rapid technology development, the rapidity of which adds risks as well as provides a major driver for costs. The National Aeronautics and Space Administration (NASA) is now approaching the extension of human presence throughout the solar system by balancing a proactive yet less schedule-driven development of technology with opportunistic scheduling of missions as the needed technologies are realized. This approach should provide cost effective, low risk technology development that will enable efficient and effective manned spaceflight missions. As a first step, the NASA Human Spaceflight Architecture Team (HAT) has identified a suite of critical technologies needed to support future manned missions across a range of destinations, including in cislunar space, near earth asteroid visits, lunar exploration, Mars space, and Mars exploration. The challenge now is to develop a strategy and plan for technology development that efficiently enables these missions over a reasonable time period, without increasing technology development costs unnecessarily due to schedule pressure, and subsequently mitigating development and mission risks. NASA fs Johnson Space Center (JSC), as the nation's primary center for human exploration, is addressing this challenge through an innovative approach allocating Internal Research and Development funding to projects that have been prioritized using four focus criteria, with appropriate importance weighting. These four focus criteria are the Human Space Flight Technology Needs, JSC Core Technology Competencies, Commercialization Potential, and Partnership Potential. The inherent coupling in these focus criteria have been captured in a database and have provided an initial prioritization for allocation of technology development research funding. This paper will describe this process and this database, and the preliminary technology development prioritization results.

Environmental restoration and waste management: Robotics technology development program: Robotics 5-year program plan. [Contains glossary

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

This plan covers robotics Research, Development, Demonstration, Testing, activities in the Program for the next five years. These activities range from bench-scale R D to fullscale hot demonstrations at DOE sites. This plan outlines applications of existing technology to near-term needs, the development and application of enhanced technology for longer-term needs, and an initiation of advanced technology development to meet those needs beyond the five-year plan. The objective of the Robotic Technology Development (RTDP) is to develop and apply robotics technologies that will enable Environmental Restoration and Waste Management operations at DOE sites to be safer, faster and cheaper. Fivemore » priority DOE sites were visited in March 1990 to identify needs for robotics technology in ER WM operations. This 5-Year Program Plan for the RTDP detailed annual plans for robotics technology development based on identified needs. This 5-Year Program Plan discusses the overall approach to be adopted by the RTDP to aggressively develop robotics technology and contains discussions of the Program Management Plan, Site Visit and Needs Summary, Approach to Needs-Directed Technical Development, Application-Specific Technical Development, and Cross-Cutting and Advanced Technology. Integrating application-specific ER WM needs, the current state of robotics technology, and the potential benefits (in terms of faster, safer, and cheaper) of new technology, the Plan develops application-specific road maps for robotics RDDT E for the period FY 1991 through FY 1995. In addition, the Plan identifies areas where longer-term research in robotics will have a high payoff in the 5- to 20-year time frame. 12 figs.« less

Summary of Research Report Cooperative Agreement

NASA Technical Reports Server (NTRS)

1997-01-01

Several areas of work related to commercialization of technology developed at NASA Ames Research Center (ARC) are discussed in this report. The areas are: (1) perform a feasibility study to develop a software commercialization center is at ARC; (2) perform preliminary work for formation of joint development of sensor technology for telemedicine applications; (3) development of a discovery interview process and staff training to assist the commercialization of technology developed at Ames, specifically aimed at working with researchers; (4) develop partners to further develop and commercialize image compression technology developed at AMES; (5) assist efforts to commercialize a software technology which imparts the ability to establish relevance-based retrieval in the handling of large repositories of information; (6) explore the development of cryocooler technology using pulse tube refrigeration; (7) assess interest in commercialization of a new method of measuring skin friction drag on wind tunnel models using liquid crystal material; (8) attempt to incorporate emerging technologies in the infrastructure of natural hazards mitigation; and (9) forming a nonprofit organization, "The Bootstrap Alliance", whose mission is to promote the use of digital technologies for collaborative problem solving. The results of these initiatives are discussed.

Technological Innovation and Developmental Strategies for Sustainable Management of Aquatic Resources in Developing Countries

NASA Astrophysics Data System (ADS)

Agboola, Julius Ibukun

2014-12-01

Sustainable use and allocation of aquatic resources including water resources require implementation of ecologically appropriate technologies, efficient and relevant to local needs. Despite the numerous international agreements and provisions on transfer of technology, this has not been successfully achieved in developing countries. While reviewing some challenges to technological innovations and developments (TID), this paper analyzes five TID strategic approaches centered on grassroots technology development and provision of localized capacity for sustainable aquatic resources management. Three case studies provide examples of successful implementation of these strategies. Success requires the provision of localized capacity to manage technology through knowledge empowerment in rural communities situated within a framework of clear national priorities for technology development.

Technological innovation and developmental strategies for sustainable management of aquatic resources in developing countries.

PubMed

Agboola, Julius Ibukun

2014-12-01

Sustainable use and allocation of aquatic resources including water resources require implementation of ecologically appropriate technologies, efficient and relevant to local needs. Despite the numerous international agreements and provisions on transfer of technology, this has not been successfully achieved in developing countries. While reviewing some challenges to technological innovations and developments (TID), this paper analyzes five TID strategic approaches centered on grassroots technology development and provision of localized capacity for sustainable aquatic resources management. Three case studies provide examples of successful implementation of these strategies. Success requires the provision of localized capacity to manage technology through knowledge empowerment in rural communities situated within a framework of clear national priorities for technology development.

Human spaceflight technology needs-a foundation for JSC's technology strategy

NASA Astrophysics Data System (ADS)

Stecklein, J. M.

Human space exploration has always been heavily influenced by goals to achieve a specific mission on a specific schedule. This approach drove rapid technology development, the rapidity of which added risks and became a major driver for costs and cost uncertainty. The National Aeronautics and Space Administration (NASA) is now approaching the extension of human presence throughout the solar system by balancing a proactive yet less schedule-driven development of technology with opportunistic scheduling of missions as the needed technologies are realized. This approach should provide cost effective, low risk technology development that will enable efficient and effective manned spaceflight missions. As a first step, the NASA Human Spaceflight Architecture Team (HAT) has identified a suite of critical technologies needed to support future manned missions across a range of destinations, including in cis-lunar space, near earth asteroid visits, lunar exploration, Mars moons, and Mars exploration. The challenge now is to develop a strategy and plan for technology development that efficiently enables these missions over a reasonable time period, without increasing technology development costs unnecessarily due to schedule pressure, and subsequently mitigating development and mission risks. NASA's Johnson Space Center (JSC), as the nation's primary center for human exploration, is addressing this challenge through an innovative approach in allocating Internal Research and Development funding to projects. The HAT Technology Needs (Tech Needs) Database has been developed to correlate across critical technologies and the NASA Office of Chief Technologist Technology Area Breakdown Structure (TABS). The TechNeeds Database illuminates that many critical technologies may support a single technical capability gap, that many HAT technology needs may map to a single TABS technology discipline, and that a single HAT technology need may map to multiple TABS technology disciplines. Th- TechNeeds Database greatly clarifies understanding of the complex relationships of critical technologies to mission and architecture element needs. Extensions to the core TechNeeds Database allow JSC to factor in and appropriately weight JSC core technology competencies, and considerations of commercialization potential and partnership potential. The inherent coupling among these, along with an appropriate importance weighting, has provided an initial prioritization for allocation of technology development research funding at JSc. The HAT Technology Needs Database, with a core of built-in reports, clarifies and communicates complex technology needs for cost effective human space exploration so that an organization seeking to assure that research prioritization supports human spaceflight of the future can be successful.

Human Spaceflight Technology Needs - A Foundation for JSC's Technology Strategy

NASA Technical Reports Server (NTRS)

Stecklein, Jonette M.

2013-01-01

Human space exploration has always been heavily influenced by goals to achieve a specific mission on a specific schedule. This approach drove rapid technology development, the rapidity of which adds risks as well as provides a major driver for costs and cost uncertainty. The National Aeronautics and Space Administration (NASA) is now approaching the extension of human presence throughout the solar system by balancing a proactive yet less schedule-driven development of technology with opportunistic scheduling of missions as the needed technologies are realized. This approach should provide cost effective, low risk technology development that will enable efficient and effective manned spaceflight missions. As a first step, the NASA Human Spaceflight Architecture Team (HAT) has identified a suite of critical technologies needed to support future manned missions across a range of destinations, including in cis-lunar space, near earth asteroid visits, lunar exploration, Mars moons, and Mars exploration. The challenge now is to develop a strategy and plan for technology development that efficiently enables these missions over a reasonable time period, without increasing technology development costs unnecessarily due to schedule pressure, and subsequently mitigating development and mission risks. NASA's Johnson Space Center (JSC), as the nation s primary center for human exploration, is addressing this challenge through an innovative approach in allocating Internal Research and Development funding to projects. The HAT Technology Needs (TechNeeds) Database has been developed to correlate across critical technologies and the NASA Office of Chief Technologist Technology Area Breakdown Structure (TABS). The TechNeeds Database illuminates that many critical technologies may support a single technical capability gap, that many HAT technology needs may map to a single TABS technology discipline, and that a single HAT technology need may map to multiple TABS technology disciplines. The TechNeeds Database greatly clarifies understanding of the complex relationships of critical technologies to mission and architecture element needs. Extensions to the core TechNeeds Database allow JSC to factor in and appropriately weight JSC Center Core Technology Competencies, and considerations of Commercialization Potential and Partnership Potential. The inherent coupling among these, along with an appropriate importance weighting, has provided an initial prioritization for allocation of technology development research funding for JSC. The HAT Technology Needs Database, with a core of built-in reports, clarifies and communicates complex technology needs for cost effective human space exploration such that an organization seeking to assure that research prioritization supports human spaceflight of the future can be successful.

Decision Gate Process for Assessment of a Technology Development Portfolio

NASA Technical Reports Server (NTRS)

Kohli, Rajiv; Fishman, Julianna; Hyatt, Mark

2012-01-01

The NASA Dust Management Project (DMP) was established to provide technologies (to TRL 6 development level) required to address adverse effects of lunar dust to humans and to exploration systems and equipment, which will reduce life cycle cost and risk, and will increase the probability of sustainable and successful lunar missions. The technology portfolio of DMP consisted of different categories of technologies whose final product is either a technology solution in itself, or one that contributes toward a dust mitigation strategy for a particular application. A Decision Gate Process (DGP) was developed to assess and validate the achievement and priority of the dust mitigation technologies as the technologies progress through the development cycle. The DGP was part of continuous technology assessment and was a critical element of DMP risk management. At the core of the process were technology-specific criteria developed to measure the success of each DMP technology in attaining the technology readiness levels assigned to each decision gate. The DGP accounts for both categories of technologies and qualifies the technology progression from technology development tasks to application areas. The process provided opportunities to validate performance, as well as to identify non-performance in time to adjust resources and direction. This paper describes the overall philosophy of the DGP and the methodology for implementation for DMP, and describes the method for defining the technology evaluation criteria. The process is illustrated by example of an application to a specific DMP technology.

Technology Development Center at NICT

NASA Technical Reports Server (NTRS)

Takefuji, Kazuhiro; Ujihara, Hideki

2013-01-01

The National Institute of Information and Communications Technology (NICT) is developing and testing VLBI technologies and conducts observations with this new equipment. This report gives an overview of the Technology Development Center (TDC) at NICT and summarizes recent activities.

Status of Sample Return Propulsion Technology Development Under NASA's ISPT Program

NASA Technical Reports Server (NTRS)

Anderson, David J.; Glaab, Louis J.; Munk, Michelle M.; Pencil, Eric; Dankanich, John; Peterson, Todd T.

2012-01-01

The In-Space Propulsion Technology (ISPT) program was tasked in 2009 to start development of propulsion technologies that would enable future sample return missions. ISPT s sample return technology development areas are diverse. Sample Return Propulsion (SRP) addresses electric propulsion for sample return and low cost Discovery-class missions, propulsion systems for Earth Return Vehicles (ERV) including transfer stages to the destination, and low technology readiness level (TRL) advanced propulsion technologies. The SRP effort continues work on HIVHAC thruster development to transition into developing a Hall-effect propulsion system for sample return (ERV and transfer stages) and low-cost missions. Previous work on the lightweight propellant-tanks continues for sample return with direct applicability to a Mars Sample Return (MSR) mission with general applicability to all future planetary spacecraft. The Earth Entry Vehicle (EEV) work focuses on building a fundamental base of multi-mission technologies for Earth Entry Vehicles (MMEEV). The main focus of the Planetary Ascent Vehicles (PAV) area is technology development for the Mars Ascent Vehicle (MAV), which builds upon and leverages the past MAV analysis and technology developments from the Mars Technology Program (MTP) and previous MSR studies

Development of Inflatable Entry Systems Technologies

NASA Technical Reports Server (NTRS)

Player, Charles J.; Cheatwood, F. McNeil; Corliss, James

2005-01-01

Achieving the objectives of NASA s Vision for Space Exploration will require the development of new technologies, which will in turn require higher fidelity modeling and analysis techniques, and innovative testing capabilities. Development of entry systems technologies can be especially difficult due to the lack of facilities and resources available to test these new technologies in mission relevant environments. This paper discusses the technology development process to bring inflatable aeroshell technology from Technology Readiness Level 2 (TRL-2) to TRL-7. This paper focuses mainly on two projects: Inflatable Reentry Vehicle Experiment (IRVE), and Inflatable Aeroshell and Thermal Protection System Development (IATD). The objectives of IRVE are to conduct an inflatable aeroshell flight test that demonstrates exoatmospheric deployment and inflation, reentry survivability and stability, and predictable drag performance. IATD will continue the development of the technology by conducting exploration specific trade studies and feeding forward those results into three more flight tests. Through an examination of these projects, and other potential projects, this paper discusses some of the risks, issues, and unexpected benefits associated with the development of inflatable entry systems technology.

[Diagnosis of the productive capacity of the IMSS regarding health technologies].

PubMed

Figueroa-Lara, Alejandro; López-Fernández, Fátima Itzel; López-Domínguez, Adriana; Fajardo-Dolci, German

To quantify the production capacity and performance in research and technological developments of the Mexican Social Security Institute (IMSS). We identified and analyzed information of the legislation, human and financial resources, and infrastructure addressed for research and technological development of IMSS. We analyzed whether the information on the legal framework contained key features to boost research and technological development. Information on the human, financial, and infrastructure resources were obtained from official sources. The research productivity was identified by a bibliometric analysis in 2014; productivity in technological developments was identified by intellectual products. The legal framework of the IMSS has several areas for improvement to boost research and technological development, especially the guidelines for technology transfer. The IMSS has 438 researchers, 39 research units, and a budget of US$ 37.4 million for research and technological development. The rate of articles published per 10 researchers was 4.8; while rate patients was 1.8. The IMSS has a great potential to translate research into technological developments, it is only necessary to make some changes to the legal framework.

Spacecraft Bus and Platform Technology Development under the NASA ISPT Program

NASA Technical Reports Server (NTRS)

Anderson, David J.; Munk, Michelle M.; Pencil, Eric; Dankanich, John; Glaab, Louis; Peterson, Todd

2013-01-01

The In-Space Propulsion Technology (ISPT) program is developing spacecraft bus and platform technologies that will enable or enhance NASA robotic science missions. The ISPT program is currently developing technology in four areas that include Propulsion System Technologies (electric and chemical), Entry Vehicle Technologies (aerocapture and Earth entry vehicles), Spacecraft Bus and Sample Return Propulsion Technologies (components and ascent vehicles), and Systems/Mission Analysis. Three technologies are ready for near-term flight infusion: 1) the high-temperature Advanced Material Bipropellant Rocket (AMBR) engine providing higher performance; 2) NASA s Evolutionary Xenon Thruster (NEXT) ion propulsion system, a 0.6-7 kW throttle-able gridded ion system; and 3) Aerocapture technology development with investments in a family of thermal protection system (TPS) materials and structures; guidance, navigation, and control (GN&C) models of blunt-body rigid aeroshells; and aerothermal effect models. Two component technologies being developed with flight infusion in mind are the Advanced Xenon Flow Control System, and ultra-lightweight propellant tank technologies. Future direction for ISPT are technologies that relate to sample return missions and other spacecraft bus technology needs like: 1) Mars Ascent Vehicles (MAV); 2) multi-mission technologies for Earth Entry Vehicles (MMEEV) for sample return missions; and 3) electric propulsion for sample return and low cost missions. These technologies are more vehicle and mission-focused, and present a different set of technology development and infusion steps beyond those previously implemented. The Systems/Mission Analysis area is focused on developing tools and assessing the application of propulsion and spacecraft bus technologies to a wide variety of mission concepts. These in-space propulsion technologies are applicable, and potentially enabling for future NASA Discovery, New Frontiers, and sample return missions currently under consideration, as well as having broad applicability to potential Flagship missions. This paper provides a brief overview of the ISPT program, describing the development status and technology infusion readiness of in-space propulsion technologies in the areas of electric propulsion, Aerocapture, Earth entry vehicles, propulsion components, Mars ascent vehicle, and mission/systems analysis.

Spacecraft Bus and Platform Technology Development under the NASA ISPT Program

NASA Technical Reports Server (NTRS)

Anderson, David J.; Munk, Michelle M.; Pencil, Eric J.; Dankanich, John W.; Glaab, Louis J.; Peterson, Todd T.

2013-01-01

The In-Space Propulsion Technology (ISPT) program is developing spacecraft bus and platform technologies that will enable or enhance NASA robotic science missions. The ISPT program is currently developing technology in four areas that include Propulsion System Technologies (electric and chemical), Entry Vehicle Technologies (aerocapture and Earth entry vehicles), Spacecraft Bus and Sample Return Propulsion Technologies (components and ascent vehicles), and Systems/Mission Analysis. Three technologies are ready for near-term flight infusion: 1) the high-temperature Advanced Material Bipropellant Rocket (AMBR) engine providing higher performance 2) NASAs Evolutionary Xenon Thruster (NEXT) ion propulsion system, a 0.6-7 kW throttle-able gridded ion system and 3) Aerocapture technology development with investments in a family of thermal protection system (TPS) materials and structures guidance, navigation, and control (GN&C) models of blunt-body rigid aeroshells and aerothermal effect models. Two component technologies being developed with flight infusion in mind are the Advanced Xenon Flow Control System, and ultra-lightweight propellant tank technologies. Future direction for ISPT are technologies that relate to sample return missions and other spacecraft bus technology needs like: 1) Mars Ascent Vehicles (MAV) 2) multi-mission technologies for Earth Entry Vehicles (MMEEV) for sample return missions and 3) electric propulsion for sample return and low cost missions. These technologies are more vehicle and mission-focused, and present a different set of technology development and infusion steps beyond those previously implemented. The Systems/Mission Analysis area is focused on developing tools and assessing the application of propulsion and spacecraft bus technologies to a wide variety of mission concepts. These in-space propulsion technologies are applicable, and potentially enabling for future NASA Discovery, New Frontiers, and sample return missions currently under consideration, as well as having broad applicability to potential Flagship missions. This paper provides a brief overview of the ISPT program, describing the development status and technology infusion readiness of in-space propulsion technologies in the areas of electric propulsion, Aerocapture, Earth entry vehicles, propulsion components, Mars ascent vehicle, and mission/systems analysis.

Development and Validation of Information Technology Mentor Teacher Attitude Scale: A Pilot Study

ERIC Educational Resources Information Center

Saltan, Fatih

2015-01-01

The aim of this study development and validation of a teacher attitude scale toward Information Technology Mentor Teachers (ITMT). ITMTs give technological support to other teachers for integration of technology in their lessons. In the literature, many instruments have been developed to measure teachers' attitudes towards the technological tools…

EPA-developed, patented technologies related to water monitoring and remediation that are available for licensing

EPA Pesticide Factsheets

Under the Federal Technology Transfer Act (FTTA), Federal Agencies can patent inventions developed during the course of research. These technologies can then be licensed to businesses or individuals for further development and sale in the marketplace. These technologies relate to water monitoring and treatment technologies.

Initial Development of the Meaningful Learning with Technology Scale (MeLTS) for High-School Students

ERIC Educational Resources Information Center

Lee, Chwee Beng

2018-01-01

With the rapid developments in emerging technologies and the emphasis on technologies in learning environments, the connection between technologies and meaningful learning has strengthened. Developing an understanding of the components of meaningful learning with technology is pivotal, as this may enable educators to make more informed decisions…

Hypersonic Inflatable Aerodynamic Decelerator (HIAD) Technology Development Overview

NASA Technical Reports Server (NTRS)

Hughes, Stephen J.; Cheatwood, F. McNeil; Calomino, Anthony M.; Wright, Henry S.; Wusk, Mary E.; Hughes, Monica F.

2013-01-01

The successful flight of the Inflatable Reentry Vehicle Experiment (IRVE)-3 has further demonstrated the potential value of Hypersonic Inflatable Aerodynamic Decelerator (HIAD) technology. This technology development effort is funded by NASA's Space Technology Mission Directorate (STMD) Game Changing Development Program (GCDP). This paper provides an overview of a multi-year HIAD technology development effort, detailing the projects completed to date and the additional testing planned for the future.

NASA Space Technology Roadmaps and Priorities: Restoring NASA's Technological Edge and Paving the Way for a New Era in Space

NASA Technical Reports Server (NTRS)

2012-01-01

Success in executing future NASA space missions will depend on advanced technology developments that should already be underway. It has been years since NASA has had a vigorous, broad-based program in advanced space technology development, and NASA's technology base is largely depleted. As noted in a recent National Research Council report on the U.S. civil space program: Future U.S. leadership in space requires a foundation of sustained technology advances that can enable the development of more capable, reliable, and lower-cost spacecraft and launch vehicles to achieve space program goals. A strong advanced technology development foundation is needed also to enhance technology readiness of new missions, mitigate their technological risks, improve the quality of cost estimates, and thereby contribute to better overall mission cost management. Yet financial support for this technology base has eroded over the years. The United States is now living on the innovation funded in the past and has an obligation to replenish this foundational element. NASA has developed a draft set of technology roadmaps to guide the development of space technologies under the leadership of the NASA Office of the Chief Technologist. The NRC appointed the Steering Committee for NASA Technology Roadmaps and six panels to evaluate the draft roadmaps, recommend improvements, and prioritize the technologies within each and among all of the technology areas as NASA finalizes the roadmaps. The steering committee is encouraged by the initiative NASA has taken through the Office of the Chief Technologist (OCT) to develop technology roadmaps and to seek input from the aerospace technical community with this study.

Teachers' perceptions of effective science, technology, and mathematics professional development and changes in classroom practices

NASA Astrophysics Data System (ADS)

Boriack, Anna Christine

The purpose of this study is to examine teachers' perceptions of professional development and changes in classroom practice. A proposed conceptual framework for effective professional development that results in changes in classroom practices was developed. Data from two programs that provided professional development to teachers in the areas of technology, mathematics, and science was used to inform the conceptual framework. These two programs were Target Technology in Texas (T3) and Mathematics, Science, and Technology Teacher Preparation Academies (MSTTPA). This dissertation used a multiple article format to explore each program separately, yet the proposed conceptual framework allowed for comparisons to be made between the two programs. The first study investigated teachers' perceptions of technology-related professional development after their districts had received a T3 grant. An online survey was administrated to all teachers to determine their perceptions of technology-related professional development along with technology self-efficacy. Classroom observations were conducted to determine if teachers were implementing technology. The results indicated that teachers did not perceive professional development as being effective and were not implementing technology in their classrooms. Teachers did have high technology self-efficacy and perceived adequate school support, which implies that effective professional development may be a large factor in whether or not teachers implement technology in their classrooms. The second study evaluated participants' perceptions of the effectiveness of mathematics and science professional development offered through a MSTTP academy. Current and former participants completed an online survey which measured their perceptions of academy activities and school environment. Participants also self-reported classroom implementation of technology. Interviews and open-ended survey questions were used to provide further insight into academy activities. The results indicated that academy participants perceived effective academy activities along with a supportive school environment. Additionally, participants reported sometimes implementing technology in their classrooms. These findings suggest that several factors might influence the successful classroom implementation of professional development. The data which supports the conceptual framework shows that effective professional development may play a key role in successful classroom implementation. Future professional development activities should be designed around characteristics for effective professional development to increase the likelihood that classroom implementation might occur.

New Strategy for Exploration Technology Development: The Human Exploration and Development of Space (HEDS) Exploration/Commercialization Technology Initiative

NASA Technical Reports Server (NTRS)

Mankins, John C.

2000-01-01

In FY 2001, NASA will undertake a new research and technology program supporting the goals of human exploration: the Human Exploration and Development of Space (HEDS) Exploration/Commercialization Technology Initiative (HTCI). The HTCI represents a new strategic approach to exploration technology, in which an emphasis will be placed on identifying and developing technologies for systems and infrastructures that may be common among exploration and commercial development of space objectives. A family of preliminary strategic research and technology (R&T) road maps have been formulated that address "technology for human exploration and development of space (THREADS). These road maps frame and bound the likely content of the HTCL Notional technology themes for the initiative include: (1) space resources development, (2) space utilities and power, (3) habitation and bioastronautics, (4) space assembly, inspection and maintenance, (5) exploration and expeditions, and (6) space transportation. This paper will summarize the results of the THREADS road mapping process and describe the current status and content of the HTCI within that framework. The paper will highlight the space resources development theme within the Initiative and will summarize plans for the coming year.

Technology transfer within the NASA Goddard Space Flight Center

NASA Technical Reports Server (NTRS)

Plotkin, Henry H.

1992-01-01

Viewgraphs on technology transfer within the NASA Goddard Space Flight Center presented to Civil Space Technology Development workshop on technology transfer and effectiveness are provided. Topics covered include: obstacles to technology transfer; technology transfer improvement program at GSFC: communication between technology developers and users; and user feedback to technologists.

The NASA Redox Storage System Development project, 1980

NASA Technical Reports Server (NTRS)

1982-01-01

The technical accomplishments pertaining to the development of Redox systems and related technology are outlined in terms of the task elements: prototype systems development, application analyses, and supporting technology. Prototype systems development provides for a major procurement to develop an industrial capability to take the current NASA Lewis technology and go on to the design, development, and commercialization of iron-chromium Redox storage systems. Application analyses provides for the definition of application concepts and technology requirements, specific definition studies, and the identification of market sectors and their penetration potential. Supporting technology includes both in house and contractual efforts that encompass implementation of technology improvements in membranes, electrodes, reactant processing, and system design. The status of all elements is discussed.

The NASA Redox Storage System Development project, 1980

NASA Astrophysics Data System (ADS)

1982-12-01

The technical accomplishments pertaining to the development of Redox systems and related technology are outlined in terms of the task elements: prototype systems development, application analyses, and supporting technology. Prototype systems development provides for a major procurement to develop an industrial capability to take the current NASA Lewis technology and go on to the design, development, and commercialization of iron-chromium Redox storage systems. Application analyses provides for the definition of application concepts and technology requirements, specific definition studies, and the identification of market sectors and their penetration potential. Supporting technology includes both in house and contractual efforts that encompass implementation of technology improvements in membranes, electrodes, reactant processing, and system design. The status of all elements is discussed.

[Patented technology status quo and development trend for Chinese herbal medicines].

PubMed

Li, Chang; Huang, Luqi

2009-06-01

Patent technology is regarded as technological trends under the market economy condition. The case showed the information form patent literature can be widely used in technology or economy. In this study, we analyzed the patent technology status quo and development trend for Chinese herbal medicines based on China patent database. The patent technology status quo is divided from the technology of biotechnology, quality control, cultivation and herb processing on Chinese herbal medicines. Furthermore, some recommendations of technology development and advices on patent protection for Chinese herbal medicines were suggested.

A Lunar Surface System Supportability Technology Development Roadmap

NASA Technical Reports Server (NTRS)

Oeftering, Richard C.; Struk, Peter M.; Taleghani, Barmac K.

2009-01-01

This paper discusses the establishment of a Supportability Technology Development Roadmap as a guide for developing capabilities intended to allow NASA's Constellation program to enable a supportable, sustainable and affordable exploration of the Moon and Mars. Presented is a discussion of "supportability", in terms of space facility maintenance, repair and related logistics and a comparison of how lunar outpost supportability differs from the International Space Station. Supportability lessons learned from NASA and Department of Defense experience and their impact on a future lunar outpost is discussed. A supportability concept for future missions to the Moon and Mars that involves a transition from a highly logistics dependent to a logistically independent operation is discussed. Lunar outpost supportability capability needs are summarized and a supportability technology development strategy is established. The resulting Lunar Surface Systems Supportability Strategy defines general criteria that will be used to select technologies that will enable future flight crews to act effectively to respond to problems and exploit opportunities in a environment of extreme resource scarcity and isolation. This strategy also introduces the concept of exploiting flight hardware as a supportability resource. The technology roadmap involves development of three mutually supporting technology categories, Diagnostics Test & Verification, Maintenance & Repair, and Scavenging & Recycling. The technology roadmap establishes two distinct technology types, "Embedded" and "Process" technologies, with different implementation and thus different criteria and development approaches. The supportability technology roadmap addresses the technology readiness level, and estimated development schedule for technology groups that includes down-selection decision gates that correlate with the lunar program milestones. The resulting supportability technology roadmap is intended to develop a set of technologies with widest possible capability and utility with a minimum impact on crew time and training and remain within the time and cost constraints of the Constellation program

A Lunar Surface System Supportability Technology Development Roadmap

NASA Technical Reports Server (NTRS)

Oeftering, Richard C.; Struk, Peter M.; Taleghani, barmac K.

2011-01-01

This paper discusses the establishment of a Supportability Technology Development Roadmap as a guide for developing capabilities intended to allow NASA s Constellation program to enable a supportable, sustainable and affordable exploration of the Moon and Mars. Presented is a discussion of supportability, in terms of space facility maintenance, repair and related logistics and a comparison of how lunar outpost supportability differs from the International Space Station. Supportability lessons learned from NASA and Department of Defense experience and their impact on a future lunar outpost is discussed. A supportability concept for future missions to the Moon and Mars that involves a transition from a highly logistics dependent to a logistically independent operation is discussed. Lunar outpost supportability capability needs are summarized and a supportability technology development strategy is established. The resulting Lunar Surface Systems Supportability Strategy defines general criteria that will be used to select technologies that will enable future flight crews to act effectively to respond to problems and exploit opportunities in an environment of extreme resource scarcity and isolation. This strategy also introduces the concept of exploiting flight hardware as a supportability resource. The technology roadmap involves development of three mutually supporting technology categories, Diagnostics Test and Verification, Maintenance and Repair, and Scavenging and Recycling. The technology roadmap establishes two distinct technology types, "Embedded" and "Process" technologies, with different implementation and thus different criteria and development approaches. The supportability technology roadmap addresses the technology readiness level, and estimated development schedule for technology groups that includes down-selection decision gates that correlate with the lunar program milestones. The resulting supportability technology roadmap is intended to develop a set of technologies with widest possible capability and utility with a minimum impact on crew time and training and remain within the time and cost constraints of the Constellation program.

Arsenic removal methods for drinking water in the developing countries: technological developments and research needs.

PubMed

Kabir, Fayzul; Chowdhury, Shakhawat

2017-11-01

Arsenic pollution of drinking water is a concern, particularly in the developing countries. Removal of arsenic from drinking water is strongly recommended. Despite the availability of efficient technologies for arsenic removal, the small and rural communities in the developing countries are not capable of employing most of these technologies due to their high cost and technical complexity. There is a need for the "low-cost" and "easy to use" technologies to protect the humans in the arsenic affected developing countries. In this study, arsenic removal technologies were summarized and the low-cost technologies were reviewed. The advantages and disadvantages of these technologies were identified and their scopes of applications and improvements were investigated. The costs were compared in context to the capacity of the low-income populations in the developing countries. Finally, future research directions were proposed to protect the low-income populations in the developing countries.

Diffusion of Appropriate Educational Technology in Open & Distance Learning in Developing Commonwealth Countries. Final Project Report.

ERIC Educational Resources Information Center

Williams, Roy

The Diffusion of Appropriate Educational Technology in Open and Distance Learning in Developing Countries project was designed to determine awareness and use of educational technologies and communications media in developing countries, to identify factors constraining wider use of educational technologies by developing nations, and to explore…

Development of High Temperature Gas Sensor Technology

NASA Technical Reports Server (NTRS)

Hunter, Gary W.; Chen, Liang-Yu; Neudeck, Philip G.; Knight, Dak; Liu, Chung-Chiun; Wu, Quing-Hai; Zhou, Huan-Jun

1997-01-01

The measurement of engine emissions is important for their monitoring and control. However, the ability to measure these emissions in-situ is limited. We are developing a family of high temperature gas sensors which are intended to operate in harsh environments such as those in an engine. The development of these sensors is based on progress in two types of technology: (1) The development of SiC-based semiconductor technology; and (2) Improvements in micromachining and microfabrication technology. These technologies are being used to develop point-contact sensors to measure gases which are important in emission control especially hydrogen, hydrocarbons, nitrogen oxides, and oxygen. The purpose of this paper is to discuss the development of this point-contact sensor technology. The detection of each type of gas involves its own challenges in the fields of materials science and fabrication technology. Of particular importance is sensor sensitivity, selectivity, and stability in long-term, high temperature operation. An overview is presented of each sensor type with an evaluation of its stage of development. It is concluded that this technology has significant potential for use in engine applications but further development is necessary.

Information Communication Technology Planning in Developing Countries

ERIC Educational Resources Information Center

Malapile, Sandy; Keengwe, Jared

2014-01-01

This article explores major issues related to Information Communication Technology (ICT) in education and technology planning. Using the diffusion of innovation theory, the authors examine technology planning opportunities and challenges in Developing countries (DCs), technology planning trends in schools, and existing technology planning models…

Technology transfer within the government

NASA Technical Reports Server (NTRS)

Russell, John

1992-01-01

The report of a workshop panel concerned with technology transfer within the government is presented. The presentation is made in vugraph form. The assigned subtopic for this panel are as follows: (1) transfer from non-NASA US government technology developers to NASA space missions/programs; and (2) transfer from NASA to other US government space mission programs. A specific area of inquiry was Technology Maturation Milestones. Three areas were investigated: technology development; advanced development; and flight hardware development.

Advanced adaptive optics technology development

NASA Astrophysics Data System (ADS)

Olivier, Scot S.

2002-02-01

The NSF Center for Adaptive Optics (CfAO) is supporting research on advanced adaptive optics technologies. CfAO research activities include development and characterization of micro-electro-mechanical systems (MEMS) deformable mirror (DM) technology, as well as development and characterization of high-resolution adaptive optics systems using liquid crystal (LC) spatial light modulator (SLM) technology. This paper presents an overview of the CfAO advanced adaptive optics technology development activities including current status and future plans.

Research and Technology: 2003 Annual Report of the John F Kennedy Space Center

NASA Technical Reports Server (NTRS)

2003-01-01

The John F. Kennedy Space Center (KSC) is America's Spaceport Technology Center. The KSC technology development program encompasses the efforts of the entire KSC team, consisting of Government and contractor personnel, working in partnership with academic institutions and commercial industry. KSC's assigned mission areas are space launch operations and spaceport and range technologies. KSC's technology development customers include current space transportation programs, future space transportation programs / initiatives, and enabling technical programs. The KSC Research and Technology 2003 Annual Report encompasses the efforts of contributors to the KSC advanced technology development program and KSC technology transfer activities. Dr. Dave Bartine, KSC Chief Technologist, (321) 867-7069, is responsible for publication of this report and should be contacted for any desired information regarding KSC's research and technology development activities.

Getting to Grips with Education and Training for Industry. A Development of the Concept of Key Technologies.

ERIC Educational Resources Information Center

Clyde, Albert

"Key technologies" is an umbrella term for appropriate technologies applied to give maximum economic benefit in particular circumstances that may cross traditional disciplinary boundaries. Development of the concept is necessitated by the rate of change of technological development. Key technologies may be classified in three groups related to…

Education in care and technology, a facilitator of interdisciplinary research and development.

PubMed

Willems, Charles G; Sponselee, Anne-Mie; Verkerke, Margreet Michel; Sirkka, Andrew; Saarni, Lea; Castello Branco, Miguel; de Witte, Luc

2015-01-01

Application of technology in care is hindered by two factors; a critical attitude of care professionals towards the use of technology as part of care delivery and a lack of knowledge of care practice by technology developers. Technological developments may provide adequate solutions to support care provision. The principles of user centred design and development, traditionally used in the development of assistive technology, may provide powerful tools to support care provision. Interdisciplinary research will be needed to take full benefit. Educational programs to support this development are lacking. Main content of this paper: Six organisations of higher education have taken the initiative to organize a training program to support professionals active in the care or in the technology domain that enables them to become involved in interdisciplinary research and development. a European program to educate a professional master in Care and Technology has been developed and is described in this paper. Accreditation of the program is initiated. Alumni of such a program may form a European network of professionals that are active in developing new solutions to support people with special needs and contribute to the generation of new business.

75 FR 57521 - Networking and Information Technology Research and Development (NITRD) Program: Draft NITRD 2010...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-21

... NATIONAL SCIENCE FOUNDATION Networking and Information Technology Research and Development (NITRD...) for Networking and Information Technology Research and Development (NITRD). ACTION: Notice, request.... SUMMARY: With this notice, the National Coordination Office for Networking and Information Technology...

Analysis of the frontier technology of agricultural IoT and its predication research

NASA Astrophysics Data System (ADS)

Han, Shuqing; Zhang, Jianhua; Zhu, Mengshuai; Wu, Jianzhai; Shen, Chen; Kong, Fantao

2017-09-01

Agricultural IoT (Internet of Things) develops rapidly. Nanotechnology, biotechnology and optoelectronic technology are successfully integrated into the agricultural sensor technology. Big data, cloud computing and artificial intelligence technology have also been successfully used in IoT. This paper carries out the research on integration of agricultural sensor technology, nanotechnology, biotechnology and optoelectronic technology and the application of big data, cloud computing and artificial intelligence technology in agricultural IoT. The advantages and development of the integration of nanotechnology, biotechnology and optoelectronic technology with agricultural sensor technology were discussed. The application of big data, cloud computing and artificial intelligence technology in IoT and their development trend were analysed.

Developing an instrument for assessing students' concepts of the nature of technology

NASA Astrophysics Data System (ADS)

Liou, Pey-Yan

2015-05-01

Background:The nature of technology has been rarely discussed despite the fact that technology plays an essential role in modern society. It is important to discuss students' concepts of the nature of technology, and further to advance their technological literacy and adaptation to modern society. There is a need to assess high school students' concepts of the nature of technology. Purpose:This study aims to engage in discourse on students' concepts of the nature of technology based on a proposed theoretical framework. Moreover, another goal is to develop an instrument for measuring students' concepts of the nature of technology. Sample:Four hundred and fifty-five high school students' perceptions of technology were qualitatively analyzed. Furthermore, 530 students' responses to a newly developed questionnaire were quantitatively analyzed in the final test. Design and method:First, content analysis was utilized to discuss and categorize students' statements regarding technology and its related issues. The Student Concepts of the Nature of Technology Questionnaire was developed based on the proposed theoretical framework and was supported by the students' qualitative data. Finally, exploratory factor analysis and reliability analysis were applied to determine the structure of the items and the internal consistency of each scale. Results:Through a process of instrument development, the Student Concepts of the Nature of Technology Questionnaire was shown to be a valid and reliable tool for measuring students' concepts of the nature of technology. This newly developed questionnaire is composed of 29 items in six scales, namely 'technology as artifacts,' 'technology as an innovation change,' 'the current role of technology in society,' 'technology as a double-edged sword,' 'technology as a science-based form,' and 'history of technology.' Conclusions:The Student Concepts of the Nature of Technology Questionnaire has been confirmed as a reasonably valid and reliable instrument. This study provides a useful questionnaire for educational researchers and practitioners for measuring students' concepts of the nature of technology.

A Study to Compare Curriculum of Computer Information Systems and Computer Education and Instructional Technologies

ERIC Educational Resources Information Center

Cavus, Nadire

2008-01-01

Today, developments of information and communication technologies have been developing very fast all over the world. These new technologies were taking an important place in education like other sciences. For this reason, education was developing parallel to new developments on the new technologies. Departments which cover curriculum of new…

Technology Development Risk Assessment for Space Transportation Systems

NASA Technical Reports Server (NTRS)

Mathias, Donovan L.; Godsell, Aga M.; Go, Susie

2006-01-01

A new approach for assessing development risk associated with technology development projects is presented. The method represents technology evolution in terms of sector-specific discrete development stages. A Monte Carlo simulation is used to generate development probability distributions based on statistical models of the discrete transitions. Development risk is derived from the resulting probability distributions and specific program requirements. Two sample cases are discussed to illustrate the approach, a single rocket engine development and a three-technology space transportation portfolio.

Solar Cell and Array Technology Development for NASA Solar Electric Propulsion Missions

NASA Technical Reports Server (NTRS)

Piszczor, Michael; McNatt, Jeremiah; Mercer, Carolyn; Kerslake, Tom; Pappa, Richard

2012-01-01

NASA is currently developing advanced solar cell and solar array technologies to support future exploration activities. These advanced photovoltaic technology development efforts are needed to enable very large (multi-hundred kilowatt) power systems that must be compatible with solar electric propulsion (SEP) missions. The technology being developed must address a wide variety of requirements and cover the necessary advances in solar cell, blanket integration, and large solar array structures that are needed for this class of missions. Th is paper will summarize NASA's plans for high power SEP missions, initi al mission studies and power system requirements, plans for advanced photovoltaic technology development, and the status of specific cell and array technology development and testing that have already been conducted.

Environmental restoration and waste management: Robotics technology development program: Robotics 5-year program plan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

This plan covers robotics Research, Development, Demonstration, Testing and Evaluation activities in the Program for the next five years. These activities range from bench-scale R D to full-scale hot demonstrations at DOE sites. This plan outlines applications of existing technology to near-term needs, the development and application of enhanced technology for longer-term needs, and initiation of advanced technology development to meet those needs beyond the five-year plan. The objective of the Robotic Technology Development Program (RTDP) is to develop and apply robotics technologies that will enable Environmental Restoration and Waste Management (ER WM) operations at DOE sites to be safer,more » faster and cheaper. Five priority DOE sites were visited in March 1990 to identify needs for robotics technology in ER WM operations. This 5-Year Program Plan for the RTDP detailed annual plans for robotics technology development based on identified needs. In July 1990 a forum was held announcing the robotics program. Over 60 organizations (industrial, university, and federal laboratory) made presentations on their robotics capabilities. To stimulate early interactions with the ER WM activities at DOE sites, as well as with the robotics community, the RTDP sponsored four technology demonstrations related to ER WM needs. These demonstrations integrated commercial technology with robotics technology developed by DOE in support of areas such as nuclear reactor maintenance and the civilian reactor waste program. 2 figs.« less

NASA's Launch Propulsion Systems Technology Roadmap

NASA Technical Reports Server (NTRS)

McConnaughey, Paul K.; Femminineo, Mark G.; Koelfgen, Syri J.; Lepsch, Roger A; Ryan, Richard M.; Taylor, Steven A.

2012-01-01

Safe, reliable, and affordable access to low-Earth (LEO) orbit is necessary for all of the United States (US) space endeavors. In 2010, NASA s Office of the Chief Technologist commissioned 14 teams to develop technology roadmaps that could be used to guide the Agency s and US technology investment decisions for the next few decades. The Launch Propulsion Systems Technology Area (LPSTA) team was tasked to address the propulsion technology challenges for access to LEO. The developed LPSTA roadmap addresses technologies that enhance existing solid or liquid propulsion technologies and their related ancillary systems or significantly advance the technology readiness level (TRL) of less mature systems like airbreathing, unconventional, and other launch technologies. In developing this roadmap, the LPSTA team consulted previous NASA, military, and industry studies as well as subject matter experts to develop their assessment of this field, which has fundamental technological and strategic impacts for US space capabilities.

A case history of technology transfer

NASA Technical Reports Server (NTRS)

1981-01-01

A sequence of events, occurring over the last 25 years, are described that chronicle the evolution of ion-bombardment electric propulsion technology. Emphasis is placed on the latter phases of this evolution, where special efforts were made to pave the way toward the use of this technology in operational space flight systems. These efforts consisted of a planned program to focus the technology toward its end applications and an organized process that was followed to transfer the technology from the research-technology NASA Center to the user-development NASA Center and its industry team. Major milestones in this evolution, which are described, include the development of thruster technology across a large size range, the successful completion of two space electric rocket tests, SERT I and SERT II, development of power-processing technology for electric propulsion, completion of a program to make the technology ready for flight system development, and finally the technology transfer events.

Technology transfer and international development: Materials and manufacturing technology

NASA Technical Reports Server (NTRS)

1982-01-01

Policy oriented studies on technological development in several relatively advanced developing countries were conducted. Priority sectors defined in terms of technological sophistication, capital intensity, value added, and export potential were studied in Brazil, Venezuela, Israel, and Korea. The development of technological policy alternatives for the sponsoring country is assessed. Much emphasis is placed on understanding the dynamics of the sectors through structured interviews with a large sample of firms in the leading manufacturing and materials processing sectors.

Decision Gate Process for Assessment of a NASA Technology Development Portfolio

NASA Technical Reports Server (NTRS)

Kohli, Rajiv; Fishman, Julianna L.; Hyatt, Mark J.

2012-01-01

The NASA Dust Management Project (DMP) was established to provide technologies (to Technology Readiness Level (TRL) 6) required to address adverse effects of lunar dust to humans and to exploration systems and equipment, to reduce life cycle cost and risk, and to increase the probability of sustainable and successful lunar missions. The technology portfolio of DMP consisted of different categories of technologies whose final product was either a technology solution in itself, or one that contributes toward a dust mitigation strategy for a particular application. A Decision Gate Process (DGP) was developed to assess and validate the achievement and priority of the dust mitigation technologies as the technologies progress through the development cycle. The DGP was part of continuous technology assessment and was a critical element of DMP risk management. At the core of the process were technology-specific criteria developed to measure the success of each DMP technology in attaining the technology readiness levels assigned to each decision gate. The DGP accounts for both categories of technologies and qualifies the technology progression from technology development tasks to application areas. The process provided opportunities to validate performance, as well as to identify non-performance in time to adjust resources and direction. This paper describes the overall philosophy of the DGP and the methodology for implementation for DMP, and describes the method for defining the technology evaluation criteria. The process is illustrated by example of an application to a specific DMP technology.

Evaluation Criteria for Solid Waste Processing Research and Technology Development

NASA Technical Reports Server (NTRS)

Levri, Julie A.; Hogan, J. A.; Alazraki, M. P.

2001-01-01

A preliminary list of criteria is proposed for evaluation of solid waste processing technologies for research and technology development (R&TD) in the Advanced Life Support (ALS) Program. Completion of the proposed list by current and prospective ALS technology developers, with regard to specific missions of interest, may enable identification of appropriate technologies (or lack thereof) and guide future development efforts for the ALS Program solid waste processing area. An attempt is made to include criteria that capture information about the technology of interest as well as its system-wide impacts. Some of the criteria in the list are mission-independent, while the majority are mission-specific. In order for technology developers to respond to mission-specific criteria, critical information must be available on the quantity, composition and state of the waste stream, the wast processing requirements, as well as top-level mission scenario information (e.g. safety, resource recovery, planetary protection issues, and ESM equivalencies). The technology readiness level (TRL) determines the degree to which a technology developer is able to accurately report on the list of criteria. Thus, a criteria-specific minimum TRL for mandatory reporting has been identified for each criterion in the list. Although this list has been developed to define criteria that are needed to direct funding of solid waste processing technologies, this list processes significant overlap in criteria required for technology selection for inclusion in specific tests or missions. Additionally, this approach to technology evaluation may be adapted to other ALS subsystems.

Educational technologies in health sciences libraries: teaching technology skills.

PubMed

Hurst, Emily J

2014-01-01

As technology rapidly changes, libraries remain go-to points for education and technology skill development. In academic health sciences libraries, trends suggest librarians provide more training on technology topics than ever before. While education and training have always been roles for librarians, providing technology training on new mobile devices and emerging systems requires class creation and training capabilities that are new to many librarians. To appeal to their users, many health sciences librarians are interested in developing technology-based classes. This column explores the question: what skills are necessary for developing and teaching technology in an academic health sciences library setting?

Educational Technologies in Health Science Libraries: Teaching Technology Skills

PubMed Central

Hurst, Emily J.

2014-01-01

As technology rapidly changes, libraries remain go-to points for education and technology skill development. In academic health sciences libraries, trends suggest librarians provide more training on technology topics than ever before. While education and training have always been roles for librarians, providing technology training on new mobile devices and emerging systems requires class creation and training capabilities that are new to many. To appeal to their users, many health sciences librarians are interested in developing technology-based classes. This column explores the question: what skills are necessary for developing and teaching technology in an academic health sciences library setting? PMID:24528269

High area rate reconnaissance (HARR) and mine reconnaissance/hunter (MR/H) exploratory development programs

NASA Astrophysics Data System (ADS)

Lathrop, John D.

1995-06-01

This paper describes the sea mine countermeasures developmental context, technology goals, and progress to date of the two principal Office of Naval Research exploratory development programs addressing sea mine reconnaissance and minehunting technology development. The first of these programs, High Area Rate Reconnaissance, is developing toroidal volume search sonar technology, sidelooking sonar technology, and associated signal processing technologies (motion compensation, beamforming, and computer-aided detection and classification) for reconnaissance and hunting against volume mines and proud bottom mines from 21-inch diameter vehicles operating in deeper waters. The second of these programs, Amphibious Operation Area Mine Reconnaissance/Hunter, is developing a suite of sensor technologies (synthetic aperture sonar, ahead-looking sonar, superconducting magnetic field gradiometer, and electro-optic sensor) and associated signal processing technologies for reconnaissance and hunting against all mine types (including buried mines) in shallow water and very shallow water from 21-inch diameter vehicles. The technologies under development by these two programs must provide excellent capabilities for mine detection, mine classification, and discrimination against false targets.

KSC Education Technology Research and Development Plan

NASA Technical Reports Server (NTRS)

Odell, Michael R. L.

2003-01-01

Educational technology is facilitating new approaches to teaching and learning science, technology, engineering, and mathematics (STEM) education. Cognitive research is beginning to inform educators about how students learn providing a basis for design of more effective learning environments incorporating technology. At the same time, access to computers, the Internet and other technology tools are becoming common features in K-20 classrooms. Encouraged by these developments, STEM educators are transforming traditional STEM education into active learning environments that hold the promise of enhancing learning. This document illustrates the use of technology in STEM education today, identifies possible areas of development, links this development to the NASA Strategic Plan, and makes recommendations for the Kennedy Space Center (KSC) Education Office for consideration in the research, development, and design of new educational technologies and applications.

Status of Propulsion Technology Development Under the NASA In-space Propulsion Technology Program

NASA Technical Reports Server (NTRS)

Anderson, David; Kamhawi, Hani; Patterson, Mike; Dankanich, John; Pencil, Eric; Pinero, Luis

2014-01-01

Since 2001, the In-Space Propulsion Technology (ISPT) program has been developing and delivering in-space propulsion technologies for NASA's Science Mission Directorate (SMD). These in-space propulsion technologies are applicable, and potentially enabling for future NASA Discovery, New Frontiers, Flagship and sample return missions currently under consideration. The ISPT program is currently developing technology in three areas that include Propulsion System Technologies, Entry Vehicle Technologies, and Systems Mission Analysis. ISPT's propulsion technologies include: 1) the 0.6-7 kW NASA's Evolutionary Xenon Thruster (NEXT) gridded ion propulsion system; 2) a 0.3-3.9kW Hall-effect electric propulsion (HEP) system for low cost and sample return missions; 3) the Xenon Flow Control Module (XFCM); 4) ultra-lightweight propellant tank technologies (ULTT); and 5) propulsion technologies for a Mars Ascent Vehicle (MAV). The HEP system is composed of the High Voltage Hall Accelerator (HiVHAc) thruster, a power processing unit (PPU), and the XFCM. NEXT and the HiVHAc are throttle-able electric propulsion systems for planetary science missions. The XFCM and ULTT are two component technologies which being developed with nearer-term flight infusion in mind. Several of the ISPT technologies are related to sample return missions needs like: MAV propulsion and electric propulsion. And finally, one focus of the SystemsMission Analysis area is developing tools that aid the application or operation of these technologies on wide variety of mission concepts. This paper provides a brief overview of the ISPT program, describing the development status and technology infusion readiness.

US/China Energy and Environmental Technology Center (EETC) international business development and technology transfer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsieh, S.T.; Atwood, T.; Qiu Daxiong

1997-12-31

Since January 1997, the US/China Energy and Environmental Technology Center (EETC) in Beijing has been jointly operated by Tulane University and Tsinghua University. EETC is established to encourage the adoption of technologies for energy production with improved environmental performance which are essential for supporting economic growth and managing the Global Warming and Climate Change issues. International cooperation is critical to insure the environmental and energy security on a global basis. For example, the US has acquired a great deal of useful experience in clean coal technology which has been demonstrated with major utilities in commercial operations. The adaption of, andmore » the installation of, clean coal technology should be given high priority. Worldwide, the continuous exchange of information and technology between developed and developing nations relating to the current and future clean coal technologies is of great importance. Developed nations which possess environmental responsive technologies and financial resources should work closely with developing nations to facilitate technology transfer and trade of technologies. International cooperation will lower the cost of deploying clean coal technologies directed toward the clean production of energy. This paper presents the updated activities of EETC on facilitating technology transfer and promoting the clean use of coal to satisfy growing energy demand in China.« less

Electro-Technologies. Guide to Standards and Implementation. Career & Technology Studies.

ERIC Educational Resources Information Center

Alberta Dept. of Education, Edmonton. Curriculum Standards Branch.

With this Career and Technologies Studies (CTS) curriculum guide, secondary students in Alberta can do the following: develop skills that can be applied in their daily lives; refine career-planning skills; develop technology-related skills in electro-technologies; enhance employability skills, especially in electro-technologies industries; and…

Making Technology Ready: Integrated Systems Health Management

NASA Technical Reports Server (NTRS)

Malin, Jane T.; Oliver, Patrick J.

2007-01-01

This paper identifies work needed by developers to make integrated system health management (ISHM) technology ready and by programs to make mission infrastructure ready for this technology. This paper examines perceptions of ISHM technologies and experience in legacy programs. Study methods included literature review and interviews with representatives of stakeholder groups. Recommendations address 1) development of ISHM technology, 2) development of ISHM engineering processes and methods, and 3) program organization and infrastructure for ISHM technology evolution, infusion and migration.

Digital technology and human development: a charter for nature conservation.

PubMed

Maffey, Georgina; Homans, Hilary; Banks, Ken; Arts, Koen

2015-11-01

The application of digital technology in conservation holds much potential for advancing the understanding of, and facilitating interaction with, the natural world. In other sectors, digital technology has long been used to engage communities and share information. Human development-which holds parallels with the nature conservation sector-has seen a proliferation of innovation in technological development. Throughout this Perspective, we consider what nature conservation can learn from the introduction of digital technology in human development. From this, we derive a charter to be used before and throughout project development, in order to help reduce replication and failure of digital innovation in nature conservation projects. We argue that the proposed charter will promote collaboration with the development of digital tools and ensure that nature conservation projects progress appropriately with the development of new digital technologies.

NASA's Exploration Technology Development Program Energy Storage Project Battery Technology Development

NASA Technical Reports Server (NTRS)

Reid, Concha M.; Miller, Thomas B.; Mercer, Carolyn R.; Jankovsky, Amy L.

2010-01-01

Technical Interchange Meeting was held at Saft America s Research and Development facility in Cockeysville, Maryland on Sept 28th-29th, 2010. The meeting was attended by Saft, contractors who are developing battery component materials under contracts awarded through a NASA Research Announcement (NRA), and NASA. This briefing presents an overview of the components being developed by the contractor attendees for the NASA s High Energy (HE) and Ultra High Energy (UHE) cells. The transition of the advanced lithium-ion cell development project at NASA from the Exploration Technology Development Program Energy Storage Project to the Enabling Technology Development and Demonstration High Efficiency Space Power Systems Project, changes to deliverable hardware and schedule due to a reduced budget, and our roadmap to develop cells and provide periodic off-ramps for cell technology for demonstrations are discussed. This meeting gave the materials and cell developers the opportunity to discuss the intricacies of their materials and determine strategies to address any particulars of the technology.

The acceptance of green technology: A case study in Sabah Development Corridor

NASA Astrophysics Data System (ADS)

Jainudin, Noor Azland; Jugah, Ivy; Ali, Awang Nasrizal Awang; Tawie, Rudy

2017-08-01

Green technology is the development and application of products, equipment and systems used to conserve the environment which minimizes the negative impact from human activities. The technology can be in the form of green buildings or renewable energy such as hydro, solar and biogas. Development in SDC is still at the early stage, hence there is a prospect to plan for proper green concept implementation. With the increasing number of construction projects particularly in the rapid developing city of Kota Kinabalu, green technology as a whole is becoming more significant as it helps to develop effective solutions to encounter global environmental issues. Although there has been lengthy discussion on the green technology, the visibility of the implementation is still yet to be seen widely in Kota Kinabalu. The implementation of green technology in construction will support dynamic growth of economic development activities, while improving the environment. Hence, it is important to develop a strategic plan to promote the use of green technology while the areas are still developing. The focus of this correlative-based approach study is to investigate the perception and implementation of green technology in Kota Kinabalu from the industrial perspectives.