Sample records for potential duration apd
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Nánási, Péter P; Magyar, János; Varró, András; Ördög, Balázs
2017-10-01
Beat-to-beat variability of cardiac action potential duration (short-term variability, SV) is a common feature of various cardiac preparations, including the human heart. Although it is believed to be one of the best arrhythmia predictors, the underlying mechanisms are not fully understood at present. The magnitude of SV is basically determined by the intensity of cell-to-cell coupling in multicellular preparations and by the duration of the action potential (APD). To compensate for the APD-dependent nature of SV, the concept of relative SV (RSV) has been introduced by normalizing the changes of SV to the concomitant changes in APD. RSV is reduced by I Ca , I Kr , and I Ks while increased by I Na , suggesting that ion currents involved in the negative feedback regulation of APD tend to keep RSV at a low level. RSV is also influenced by intracellular calcium concentration and tissue redox potential. The clinical implications of APD variability is discussed in detail.
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Hardy, Matthew E L; Pervolaraki, Eleftheria; Bernus, Olivier; White, Ed
2018-01-01
We investigated the steepened dynamic action potential duration (APD) restitution of rats with pulmonary artery hypertension (PAH) and right ventricular (RV) failure and tested whether the observed APD restitution properties were responsible for negative mechanical restitution in these myocytes. PAH and RV failure were provoked in male Wistar rats by a single injection of monocrotaline (MCT) and compared with saline-injected animals (CON). Action potentials were recorded from isolated RV myocytes at stimulation frequencies between 1 and 9 Hz. Action potential waveforms recorded at 1 Hz were used as voltage clamp profiles (action potential clamp) at stimulation frequencies between 1 and 7 Hz to evoke rate-dependent currents. Voltage clamp profiles mimicking typical CON and MCT APD restitution were applied and cell shortening simultaneously monitored. Compared with CON myocytes, MCT myocytes were hypertrophied; had less polarized diastolic membrane potentials; had action potentials that were triggered by decreased positive current density and shortened by decreased negative current density; APD was longer and APD restitution steeper. APD90 restitution was unchanged by exposure to the late Na + -channel blocker (5 μM) ranolazine or the intracellular Ca 2+ buffer BAPTA. Under AP clamp, stimulation frequency-dependent inward currents were smaller in MCT myocytes and were abolished by BAPTA. In MCT myocytes, increasing stimulation frequency decreased contraction amplitude when depolarization duration was shortened, to mimic APD restitution, but not when depolarization duration was maintained. We present new evidence that the membrane potential of PAH myocytes is less stable than normal myocytes, being more easily perturbed by external currents. These observations can explain increased susceptibility to arrhythmias. We also present novel evidence that negative APD restitution is at least in part responsible for the negative mechanical restitution in PAH myocytes. Thus, our study links electrical restitution remodeling to a defining mechanical characteristic of heart failure, the reduced ability to respond to an increase in demand.
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Zhao, Yuhui; Huang, Haixia; Du, Yunhui; Li, Xiao; Lv, Tingting; Zhang, Suli; Wei, Hua; Shang, Jianyu; Liu, Ping; Liu, Huirong
2015-01-01
β1-Adrenoceptor autoantibodies (β1-AAs) affect the action potential duration (APD) in cardiomyocytes and are related to ventricular arrhythmias. The delayed rectifier potassium current (I K) plays a crucial role in APD, but the effects of β1-AAs on I K have not been completely illuminated. This work aimed to observe the effects of β1-AAs on I K and APD and further explore the mechanisms of β1-AA-mediated ventricular arrhythmias. β1-AAs were obtained from sera of patients with coronary heart disease (CHD) and nonsustained ventricular tachycardia. With whole-cell patch clamp technique, action potentials and I K were recorded. The results illustrated 0.1 μmol/L β1-AAs shortened APD at 50 % (APD50) and 90 % (APD90) of the repolarization. However, at 0.01 μmol/L, β1-AAs had no effects on either APD90 or APD50 (P > 0.05). At 0.001 μmol/L, β1-AAs significantly prolonged APD90 and APD50. Moreover, β1-AAs (0.001, 0.01, 0.1 μmol/L) dose-dependently increased the rapidly activating delayed rectifier potassium current (I Kr), but similarly decreased the slowly activating delayed rectifier potassium current (I Ks) and increased L-type calcium currents at the different concentrations. Taken together, the IKr increase induced by high β1-AA concentrations is responsible for a significant APD reduction which would contribute to repolarization changes and trigger the malignant ventricular arrhythmias in CHD patients.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Park, Mi-Hyeong; Park, Won Sun; Jo, Su-Hyun, E-mail: suhyunjo@kangwon.ac.kr
2012-07-01
Polychlorinated biphenyls (PCBs) have been known as serious persistent organic pollutants (POPs), causing developmental delays and motor dysfunction. We have investigated the effects of two PCB congeners, 3,3′,4,4′-tetrachlorobiphenyl (PCB 77) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) on ECG, action potential, and the rapidly activating delayed rectifier K{sup +} current (I{sub Kr}) of guinea pigs' hearts, and hERG K{sup +} current expressed in Xenopus oocytes. PCB 126 shortened the corrected QT interval (QTc) of ECG and decreased the action potential duration at 90% (APD{sub 90}), and 50% of repolarization (APD{sub 50}) (P < 0.05) without changing the action potential duration at 20% (APD{submore » 20}). PCB 77 decreased APD{sub 20} (P < 0.05) without affecting QTc, APD{sub 90}, and APD{sub 50}. The PCB 126 increased the I{sub Kr} in guinea-pig ventricular myocytes held at 36 °C and hERG K{sup +} current amplitude at the end of the voltage steps in voltage-dependent mode (P < 0.05); however, PCB 77 did not change the hERG K{sup +} current amplitude. The PCB 77 increased the diastolic Ca{sup 2+} and decreased Ca{sup 2+} transient amplitude (P < 0.05), however PCB 126 did not change. The results suggest that PCB 126 shortened the QTc and decreased the APD{sub 90} possibly by increasing I{sub Kr}, while PCB 77 decreased the APD{sub 20} possibly by other modulation related with intracellular Ca{sup 2+}. The present data indicate that the environmental toxicants, PCBs, can acutely affect cardiac electrophysiology including ECG, action potential, intracellular Ca{sup 2+}, and channel activity, resulting in toxic effects on the cardiac function in view of the possible accumulation of the PCBs in human body. -- Highlights: ► PCBs are known as serious environmental pollutants and developmental disruptors. ► PCB 126 shortened QT interval of ECG and action potential duration. ► PCB 126 increased human ether-a-go-go-related K{sup +} current and I{sub Kr}. ► PCB 77 decreased action potential duration and increased intracellular Ca{sup 2+} content. ► PCBs acutely change cardiac electrophysiology and rhythmicity.« less
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Li, S N; Zhang, K Y
1992-11-01
Effects of dauricine (Dau) on the action potentials (AP), the slow action potentials (SAP), and the slow inward currents (Isi) of guinea pig ventricular papillary muscles were observed by means of intracellular microelectrode and single sucrose gap voltage clamp technique. In the early stage, Dau shortened action potential duration 100 (APD100) and effective refractory period (ERP) (ERP/APD < 1; P < 0.01), but did not affect APD20 and other parameters. In the late stage, Dau prolonged APD100, ERP, and APD20, significantly decreased action potential amplitude (APA), maximum velocity (Vmax), and overshot (OS) (ERP/APD > 1; P < 0.01), greatly diminished APA and OS of SAP induced by isoprenaline (P < 0.01), and remarkably inhibited Isi (P < 0.01). The results suggested that Dau exerted an inhibitory effect on Na+, Ca2+, and K+ channels.
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Restitution slope is principally determined by steady-state action potential duration.
Shattock, Michael J; Park, Kyung Chan; Yang, Hsiang-Yu; Lee, Angela W C; Niederer, Steven; MacLeod, Kenneth T; Winter, James
2017-06-01
The steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF. Experiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM - to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope. Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology
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Restitution slope is principally determined by steady-state action potential duration
Shattock, Michael J.; Park, Kyung Chan; Yang, Hsiang-Yu; Lee, Angela W. C.; Niederer, Steven; MacLeod, Kenneth T.
2017-01-01
Aims The steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF. Methods and results Experiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM – to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope. Conclusion(s) Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death. PMID:28371805
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Arteyeva, Natalia V; Azarov, Jan E
The aim of the study was to differentiate the effect of dispersion of repolarization (DOR) and action potential duration (APD) on T-wave parameters being considered as indices of DOR, namely, Tpeak-Tend interval, T-wave amplitude and T-wave area. T-wave was simulated in a wide physiological range of DOR and APD using a realistic rabbit model based on experimental data. A simplified mathematical formulation of T-wave formation was conducted. Both the simulations and the mathematical formulation showed that Tpeak-Tend interval and T-wave area are linearly proportional to DOR irrespectively of APD range, while T-wave amplitude is non-linearly proportional to DOR and inversely proportional to the minimal repolarization time, or minimal APD value. Tpeak-Tend interval and T-wave area are the most accurate DOR indices independent of APD. T-wave amplitude can be considered as an index of DOR when the level of APD is taken into account. Copyright © 2017 Elsevier Inc. All rights reserved.
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Gibson, John K; Yue, Yimei; Bronson, Jared; Palmer, Cassie; Numann, Randy
2014-01-01
It has been proposed that proarrhythmia assessment for safety pharmacology testing includes the use of human pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to detect drug-induced changes in cardiac electrophysiology. This study measured the actions of diverse agents on action potentials (AP) and ion currents recorded from hiPSC-CM. During AP experiments, the hiPSC-CM were paced at 1Hz during a baseline period, and when increasing concentrations of test compound were administered at 4-minute intervals. AP parameters, including duration (APD60 and APD90), resting membrane potential, rate of rise, and amplitude, were measured throughout the entire experiment. Voltage clamp experiments with E-4031 and nifedipine were similarly conducted. E-4031 produced a dose-dependent prolongation of cardiac action potential and blocked the hERG/IKr current with an IC50 of 17nM. At 3nM, dofetilide significantly increased APD90. Astemizole significantly increased APD60 and APD90 at 30nM. Terfenadine significantly increased APD90 at concentrations greater than 10nM. Fexofenadine, a metabolite of terfenadine, did not produce any electrophysiologic changes in cardiac action potentials. Flecainide produced a dose-dependent prolongation of the cardiac action potential at 1 and 3μM. Acute exposure to nifedipine significantly decreased APD60 and APD90 and produced a dose-dependent block of calcium current with an IC50 of 0.039μM. Verapamil first shortened APD60 and APD90 in a dose-dependent manner, until a compensating increase in APD90, presumably via hERG blockade, was observed at 1 and 3μM. Following a chronic exposure (20-24h) to clinically relevant levels of pentamidine, a significant increase in action potential duration was accompanied by early afterdepolarizations (EADs). These experiments show the ability of AP measured from hiPSC-CM to record the interactions of various ion channels via AP recording and avoid the limitations of using several single ion channel assays in a noncardiac tissue. Copyright © 2014 Elsevier Inc. All rights reserved.
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Stimers, Joseph R; Song, Li; Rusch, Nancy J; Rhee, Sung W
2015-01-01
Long QT syndrome is characterized by a prolongation of the interval between the Q wave and the T wave on the electrocardiogram. This abnormality reflects a prolongation of the ventricular action potential caused by a number of genetic mutations or a variety of drugs. Since effective treatments are unavailable, we explored the possibility of using cardiac expression of the large-conductance, Ca2+-activated K+ (BK) channel to shorten action potential duration (APD). We hypothesized that expression of the pore-forming α subunit of human BK channels (hBKα) in HL-1 cells would shorten action potential duration in this mouse atrial cell line. Expression of hBKα had minimal effects on expression levels of other ion channels with the exception of a small but significant reduction in Kv11.1. Patch-clamped hBKα expressing HL-1 cells exhibited an outward voltage- and Ca2+-sensitive K+ current, which was inhibited by the BK channel blocker iberiotoxin (100 nM). This BK current phenotype was not detected in untransfected HL-1 cells or in HL-1 null cells sham-transfected with an empty vector. Importantly, APD in hBKα-expressing HL-1 cells averaged 14.3 ± 2.8 ms (n = 10), which represented a 53% reduction in APD compared to HL-1 null cells lacking BKα expression. APD in the latter cells averaged 31.0 ± 5.1 ms (n = 13). The shortened APD in hBKα-expressing cells was restored to normal duration by 100 nM iberiotoxin, suggesting that a repolarizing K+ current attributed to BK channels accounted for action potential shortening. These findings provide initial proof-of-concept that the introduction of hBKα channels into a cardiac cell line can shorten APD, and raise the possibility that gene-based interventions to increase hBKα channels in cardiac cells may hold promise as a therapeutic strategy for long QT syndrome.
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Wang, Xinrui; Fitts, Robert H
2017-08-01
Regular exercise training is known to affect the action potential duration (APD) and improve heart function, but involvement of β-adrenergic receptor (β-AR) subtypes and/or the ATP-sensitive K + (K ATP ) channel is unknown. To address this, female and male Sprague-Dawley rats were randomly assigned to voluntary wheel-running or control groups; they were anesthetized after 6-8 wk of training, and myocytes were isolated. Exercise training significantly increased APD of apex and base myocytes at 1 Hz and decreased APD at 10 Hz. Ca 2+ transient durations reflected the changes in APD, while Ca 2+ transient amplitudes were unaffected by wheel running. The nonselective β-AR agonist isoproterenol shortened the myocyte APD, an effect reduced by wheel running. The isoproterenol-induced shortening of APD was largely reversed by the selective β 1 -AR blocker atenolol, but not the β 2 -AR blocker ICI 118,551, providing evidence that wheel running reduced the sensitivity of the β 1 -AR. At 10 Hz, the K ATP channel inhibitor glibenclamide prolonged the myocyte APD more in exercise-trained than control rats, implicating a role for this channel in the exercise-induced APD shortening at 10 Hz. A novel finding of this work was the dual importance of altered β 1 -AR responsiveness and K ATP channel function in the training-induced regulation of APD. Of physiological importance to the beating heart, the reduced response to adrenergic agonists would enhance cardiac contractility at resting rates, where sympathetic drive is low, by prolonging APD and Ca 2+ influx; during exercise, an increase in K ATP channel activity would shorten APD and, thus, protect the heart against Ca 2+ overload or inadequate filling. NEW & NOTEWORTHY Our data demonstrated that regular exercise prolonged the action potential and Ca 2+ transient durations in myocytes isolated from apex and base regions at 1-Hz and shortened both at 10-Hz stimulation. Novel findings were that wheel running shifted the β-adrenergic receptor agonist dose-response curve rightward compared with controls by reducing β 1 -adrenergic receptor responsiveness and that, at the high activation rate, myocytes from trained animals showed higher K ATP channel function. Copyright © 2017 the American Physiological Society.
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Sun, Juan; Yan, Huang; Wugeti, Najina; Guo, Yujun; Zhang, Ling; Ma, Mei; Guo, Xingui; Jiao, Changan; Xu, Wenli; Li, Tianqi
2015-01-01
Atrial fibrillation (AF) arises from abnormalities in atrial structure and electrical activity. Microelectrode arrays (MEA) is a real-time, nondestructive measurement of the resting and action potential signal, from myocardial cells, to the peripheral circuit of electrophysiological activity. This study examined the field action potential duration (fAPD) of the right atrial appendage (RAA) by MEA in rapid atrial pacing (RAP) in the right atrium of rabbits. In addition, this study also investigated the effect of potassium ion channel blockers on fAPD. 40 New Zealand white rabbits of either sex were randomly divided into 3 groups: 1) the control, 2) potassium ion channel blocker (TEA, 4-Ap and BaCl2), and 3) amiodarone groups. The hearts were quickly removed and right atrial appendage sectioned (slice thickness 500 μm). Each slice was perfused with Tyrode's solution and continuously stimulated for 30 minutes. Sections from the control group were superfused with Tyrode's solution for 10 minutes, while the blocker groups and amiodarone were both treated with their respective compounds for 10 minutes each. The fAPD of RAA and action field action potential morphology were measured using MEA. In non-pace (control) groups, fAPD was 188.33 ± 18.29 ms after Tyrode's solution superfusion, and 173.91 ± 6.83 ms after RAP. In pace/potassium ion channel groups, TEA and BaCl2 superfusion prolonged atrial field action potential (fAPD) (control vs blocker: 176.67 ± 8.66 ms vs 196.11 ± 10.76 ms, 182.22 ± 12.87 ms vs 191.11 ± 13.09 ms with TEA and BaCl2 superfusion, respectively, P < 0.05). 4-AP superfusion significantly prolonged FAPD. In pace/amiodarone groups, 4-Ap superfusion extended fAPD. MEA was a sensitive and stable reporter for the measurement of the tissue action potential in animal heart slices. After superfusing potassium ion channel blockers, fAPD was prolonged. These results suggest that Ito, IKur and IK1 remodel and mediate RAP-induced atrial electrical remodeling. Amiodarone alter potassium ion channel activity (Ito, IKur, IK1 and IKs), shortening fAPD.
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Kistamás, Kornél; Hegyi, Bence; Váczi, Krisztina; Horváth, Balázs; Bányász, Tamás; Magyar, János; Szentandrássy, Norbert; Nánási, Péter P
2015-07-01
Profound changes in tissue redox potential occur in the heart under conditions of oxidative stress frequently associated with cardiac arrhythmias. Since beat-to-beat variability (short term variability, SV) of action potential duration (APD) is a good indicator of arrhythmia incidence, the aim of this work was to study the influence of redox changes on SV in isolated canine ventricular cardiomyocytes using a conventional microelectrode technique. The redox potential was shifted toward a reduced state using a reductive cocktail (containing dithiothreitol, glutathione, and ascorbic acid) while oxidative changes were initiated by superfusion with H2O2. Redox effects were evaluated as changes in "relative SV" determined by comparing SV changes with the concomitant APD changes. Exposure of myocytes to the reductive cocktail decreased SV significantly without any detectable effect on APD. Application of H2O2 increased both SV and APD, but the enhancement of SV was the greater, so relative SV increased. Longer exposure to H2O2 resulted in the development of early afterdepolarizations accompanied by tremendously increased SV. Pretreatment with the reductive cocktail prevented both elevation in relative SV and the development of afterdepolarizations. The results suggest that the increased beat-to-beat variability during an oxidative stress contributes to the generation of cardiac arrhythmias.
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Sung, Derrick; Mills, Robert W; Schettler, Jan; Narayan, Sanjiv M; Omens, Jeffrey H; McCulloch, Andrew D
2003-07-01
Mechanical stimulation can induce electrophysiologic changes in cardiac myocytes, but how mechanoelectric feedback in the intact heart affects action potential propagation remains unclear. Changes in action potential propagation and repolarization with increased left ventricular end-diastolic pressure from 0 to 30 mmHg were investigated using optical mapping in isolated perfused rabbit hearts. With respect to 0 mmHg, epicardial strain at 30 mmHg in the anterior left ventricle averaged 0.040 +/- 0.004 in the muscle fiber direction and 0.032 +/- 0.006 in the cross-fiber direction. An increase in ventricular loading increased average epicardial activation time by 25%+/- 3% (P < 0.0001) and correspondingly decreased average apparent surface conduction velocity by 16%+/- 7% (P = 0.007). Ventricular loading did not significantly alter action potential duration at 20% repolarization (APD20) but did at 80% repolarization (APD80), from 179 +/- 7 msec to 207 +/- 5 msec (P < 0.0001). The dispersion of APD20 was decreased with loading from 19 +/- 2 msec to 13 +/- 2 msec (P = 0.024), whereas the dispersion of APD80 was not significantly changed. These electrophysiologic changes with ventricular loading were not affected by the nonspecific stretch-activated channel blocker streptomycin (200 microM) and were not attributable to changes in myocardial perfusion or the presence of an electromechanical decoupling agent (butanedione monoxime) during optical mapping. Acute loading of the left ventricle of the isolated rabbit heart decreased apparent epicardial conduction velocity and increased action potential duration by a load-dependent mechanism that may not involve stretch-activated channels.
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Campbell, Katherine; Calvo, Conrado J; Mironov, Sergey; Herron, Todd; Berenfeld, Omer; Jalife, José
2012-12-15
Spatial dispersion of action potential duration (APD) is a substrate for the maintenance of cardiac fibrillation, but the mechanisms are poorly understood. We investigated the role played by spatial APD dispersion in fibrillatory dynamics. We used an in vitro model in which spatial gradients in the expression of ether-à-go-go-related (hERG) protein, and thus rapid delayed rectifying K(+) current (I(Kr)) density, served to generate APD dispersion, high-frequency rotor formation, wavebreak and fibrillatory conduction. A unique adenovirus-mediated magnetofection technique generated well-controlled gradients in hERG and green fluorescent protein (GFP) expression in neonatal rat ventricular myocyte monolayers. Computer simulations using a realistic neonatal rat ventricular myocyte monolayer model provided crucial insight into the underlying mechanisms. Regional hERG overexpression shortened APD and increased rotor incidence in the hERG overexpressing region. An APD profile at 75 percent repolarization with a 16.6 ± 0.72 ms gradient followed the spatial profile of hERG-GFP expression; conduction velocity was not altered. Rotors in the infected region whose maximal dominant frequency was 12.9 Hz resulted in wavebreak at the interface (border zone) between infected and non-infected regions; dominant frequency distribution was uniform when the maximal dominant frequency was <12.9 Hz or the rotors resided in the uninfected region. Regularity at the border zone was lowest when rotors resided in the infected region. In simulations, a fivefold regional increase in I(Kr) abbreviated the APD and hyperpolarized the resting potential. However, the steep APD gradient at the border zone proved to be the primary mechanism of wavebreak and fibrillatory conduction. This study provides insight at the molecular level into the mechanisms by which spatial APD dispersion contributes to wavebreak, rotor stabilization and fibrillatory conduction.
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Campbell, Katherine; Calvo, Conrado J; Mironov, Sergey; Herron, Todd; Berenfeld, Omer; Jalife, José
2012-01-01
Spatial dispersion of action potential duration (APD) is a substrate for the maintenance of cardiac fibrillation, but the mechanisms are poorly understood. We investigated the role played by spatial APD dispersion in fibrillatory dynamics. We used an in vitro model in which spatial gradients in the expression of ether-à-go-go-related (hERG) protein, and thus rapid delayed rectifying K+ current (IKr) density, served to generate APD dispersion, high-frequency rotor formation, wavebreak and fibrillatory conduction. A unique adenovirus-mediated magnetofection technique generated well-controlled gradients in hERG and green fluorescent protein (GFP) expression in neonatal rat ventricular myocyte monolayers. Computer simulations using a realistic neonatal rat ventricular myocyte monolayer model provided crucial insight into the underlying mechanisms. Regional hERG overexpression shortened APD and increased rotor incidence in the hERG overexpressing region. An APD profile at 75 percent repolarization with a 16.6 ± 0.72 ms gradient followed the spatial profile of hERG-GFP expression; conduction velocity was not altered. Rotors in the infected region whose maximal dominant frequency was ≥12.9 Hz resulted in wavebreak at the interface (border zone) between infected and non-infected regions; dominant frequency distribution was uniform when the maximal dominant frequency was <12.9 Hz or the rotors resided in the uninfected region. Regularity at the border zone was lowest when rotors resided in the infected region. In simulations, a fivefold regional increase in IKr abbreviated the APD and hyperpolarized the resting potential. However, the steep APD gradient at the border zone proved to be the primary mechanism of wavebreak and fibrillatory conduction. This study provides insight at the molecular level into the mechanisms by which spatial APD dispersion contributes to wavebreak, rotor stabilization and fibrillatory conduction. PMID:23090949
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Child, Nicholas; Hanson, Ben; Bishop, Martin; Rinaldi, Christopher A; Bostock, Julian; Western, David; Cooklin, Michael; O’Neil, Mark; Wright, Matthew; Razavi, Reza; Gill, Jaswinder; Taggart, Peter
2014-01-01
Background Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported. Methods and Results Activation recovery intervals (ARI) measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady state pacing while subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Haemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (p=0.001). APD decreased during the stressful parts of the film clip, eg for global RV ARI at end of film clip 193.8ms (SD 14) vs 198.0ms (SD13) during the matched breathing control (end film LV 199.8ms (SD16) vs control 201.6ms (SD15), p=0.004. Respiration rate increased during the stressful part of the film clip (by 2 breaths/minute), and was well matched in the respective control period without any haemodynamic or ARI changes. Conclusions Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular action potential duration in conscious humans. The effect of mental challenge on APD was not secondary to emotionally-induced altered respiration or heart rate. PMID:24833641
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Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour.
Trenor, Beatriz; Cardona, Karen; Saiz, Javier; Noble, Denis; Giles, Wayne
2017-11-01
In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs). © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.
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2018-01-01
Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates. PMID:29352276
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Osadchii, Oleg E
2018-01-01
Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.
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Odening, Katja E; Jung, Bernd A; Lang, Corinna N; Cabrera Lozoya, Rocio; Ziupa, David; Menza, Marius; Relan, Jatin; Franke, Gerlind; Perez Feliz, Stefanie; Koren, Gideon; Zehender, Manfred; Bode, Christoph; Brunner, Michael; Sermesant, Maxime; Föll, Daniela
2013-10-01
Enhanced dispersion of action potential duration (APD) is a major contributor to long QT syndrome (LQTS)-related arrhythmias. To investigate spatial correlations of regional heterogeneities in cardiac repolarization and mechanical function in LQTS. Female transgenic LQTS type 2 (LQT2; n = 11) and wild-type littermate control (LMC) rabbits (n = 9 without E4031 and n = 10 with E4031) were subjected to phase contrast magnetic resonance imaging to assess regional myocardial velocities. In the same rabbits' hearts, monophasic APDs were assessed in corresponding segments. In LQT2 and E4031-treated rabbits, APD was longer in all left ventricular segments (P < .01) and APD dispersion was greater than that in LMC rabbits (P < .01). In diastole, peak radial velocities (Vr) were reduced in LQT2 and E4031-treated compared to LMC rabbits in LV base and mid (LQT2: -3.36 ± 0.4 cm/s, P < .01; E4031-treated: -3.24 ± 0.6 cm/s, P < .0001; LMC: -4.42 ± 0.5 cm/s), indicating an impaired diastolic function. Regionally heterogeneous diastolic Vr correlated with APD (LQT2: correlation coefficient [CC] 0.38, P = .01; E4031-treated: CC 0.42, P < .05). Time-to-diastolic peak Vr were prolonged in LQT2 rabbits (LQT2: 196.8 ± 2.9 ms, P < .001; E4031-treated: 199.5 ± 2.2 ms, P < .0001, LMC 183.1 ± 1.5), indicating a prolonged contraction duration. Moreover, in transgenic LQT2 rabbits, diastolic time-to-diastolic peak Vr correlated with APD (CC 0.47, P = .001). In systole, peak Vr were reduced in LQT2 and E4031-treated rabbits (P < .01) but longitudinal velocities or ejection fraction did not differ. Finally, random forest machine learning algorithms enabled a differentiation between LQT2, E4031-treated, and LMC rabbits solely based on "mechanical" magnetic resonance imaging data. The prolongation of APD led to impaired diastolic and systolic function in transgenic and drug-induced LQT2 rabbits. APD correlated with regional diastolic dysfunction, indicating that LQTS is not purely an electrical but an electromechanical disorder. © 2013 Heart Rhythm Society. All rights reserved.
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Kuusela, Jukka; Larsson, Kim; Shah, Disheet; Prajapati, Chandra; Aalto-Setälä, Katriina
2017-06-15
Long QT syndrome (LQTS) is characterized by a prolonged QT-interval on electrocardiogram and by increased risk of sudden death. One of the most common and potentially life-threatening electrolyte disturbances is hypokalemia, characterized by low concentrations of K + Using a multielectrode array platform and current clamp technique, we investigated the effect of low extracellular K + concentration ([K + ] Ex ) on the electrophysiological properties of hiPSC-derived cardiomyocytes (CMs) generated from a healthy control subject (WT) and from two symptomatic patients with type 1 of LQTS carrying G589D (LQT1A) or IVS7-2A>G mutation (LQT1B) in KCNQ1 The baseline prolongations of field potential durations (FPDs) and action potential durations (APDs) were longer in LQT1-CMs than in WT-CMs. Exposure to low [K + ] Ex prolonged FPDs and APDs in a concentration-dependent fashion. LQT1-CMs were found to be more sensitive to low [K + ] Ex compared to WT-CMs. At baseline, LQT1A-CMs had more prolonged APDs than LQT1B-CMs, but low [K + ] Ex caused more pronounced APD prolongation in LQT1B-CMs. Early afterdepolarizations in the action potentials were observed in a subset of LQT1A-CMs with further prolonged baseline APDs and triangular phase 2 profiles. This work demonstrates that the hiPSC-derived CMs are sensitive to low [K + ] Ex and provide a platform to study acquired LQTS. © 2017. Published by The Company of Biologists Ltd.
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NASA Technical Reports Server (NTRS)
Sung, Derrick; Mills, Robert W.; Schettler, Jan; Narayan, Sanjiv M.; Omens, Jeffrey H.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)
2003-01-01
INTRODUCTION: Mechanical stimulation can induce electrophysiologic changes in cardiac myocytes, but how mechanoelectric feedback in the intact heart affects action potential propagation remains unclear. METHODS AND RESULTS: Changes in action potential propagation and repolarization with increased left ventricular end-diastolic pressure from 0 to 30 mmHg were investigated using optical mapping in isolated perfused rabbit hearts. With respect to 0 mmHg, epicardial strain at 30 mmHg in the anterior left ventricle averaged 0.040 +/- 0.004 in the muscle fiber direction and 0.032 +/- 0.006 in the cross-fiber direction. An increase in ventricular loading increased average epicardial activation time by 25%+/- 3% (P < 0.0001) and correspondingly decreased average apparent surface conduction velocity by 16%+/- 7% (P = 0.007). Ventricular loading did not significantly alter action potential duration at 20% repolarization (APD20) but did at 80% repolarization (APD80), from 179 +/- 7 msec to 207 +/- 5 msec (P < 0.0001). The dispersion of APD20 was decreased with loading from 19 +/- 2 msec to 13 +/- 2 msec (P = 0.024), whereas the dispersion of APD80 was not significantly changed. These electrophysiologic changes with ventricular loading were not affected by the nonspecific stretch-activated channel blocker streptomycin (200 microM) and were not attributable to changes in myocardial perfusion or the presence of an electromechanical decoupling agent (butanedione monoxime) during optical mapping. CONCLUSION: Acute loading of the left ventricle of the isolated rabbit heart decreased apparent epicardial conduction velocity and increased action potential duration by a load-dependent mechanism that may not involve stretch-activated channels.
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Cherry, Elizabeth M.; Fenton, Flavio H.
2011-01-01
Increased dispersion of action potential duration across cardiac tissue has long been considered an important substrate for the development of most electrical arrhythmias. Although this dispersion has been studied previously by characterizing the static intrinsic gradients in cellular electrophysiology and dynamical gradients generated by fast pacing, few studies have concentrated on dispersions generated solely by structural effects. Here we show how boundaries and geometry can produce spatially dependent changes in action potential duration (APD) in homogeneous and isotropic tissue, where all the cells have the same APD in the absence of diffusion. Electrotonic currents due to coupling within the tissue and at the tissue boundaries can generate dispersion, and the profile of this dispersion can change dramatically depending on tissue size and shape, action potential morphology, tissue dimensionality, and stimulus frequency and location. The dispersion generated by pure geometrical effects can be on the order of tens of milliseconds, enough under certain conditions to produce conduction blocks and initiate reentrant waves. PMID:21762703
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Lan, Yun-Feng; Zhang, Jian-Cheng; Gao, Jin-Lao; Wang, Xue-Ping; Fang, Zhou; Fu, Yi-Cheng; Chen, Mei-Yan; Lin, Min; Xue, Qiao; Li, Yang
2013-01-01
Objectives To investigate the effect of nerve growth factor (NGF) on the action potential and potassium currents of non-infarcted myocardium in the myocardial infarcted rabbit model. Methods Rabbits with occlusion of the left anterior descending coronary artery were prepared and allowed to recover for eight weeks (healed myocardial infarction, HMI). During ligation surgery of the left coronary artery, a polyethylene tube was placed near the left stellate ganglion in the subcutis of the neck for the purpose of administering NGF 400 U/d for eight weeks (HMI + NGF group). Cardiomyocytes were isolated from regions of the non-infarcted left ventricular wall and the action potentials and ion currents in these cells were recorded using whole-cell patch clamps. Results Compared with HMI and control cardiomyocytes, significant prolongation of APD50 or APD90 (Action potential duration (APD) measured at 50% and 90% of repolarization) in HMI + NGF cardiomyocytes was found. The results showed that the 4-aminopyridine sensitive transient outward potassium current (Ito), the rapidly activated omponent of delayed rectifier potassium current (IKr), the slowly activated component of delayed rectifier potassium current (IKs), and the L-type calcium current (ICaL) were significantly altered in NGF + HMI cardiomyocytes compared with HMI and control cells. Conclusions Our results suggest that NGF treatment significantly prolongs APD in HMI cardiomyocytes and that a decrease in outward potassium currents and an increase of inward Ca2+ current are likely the underlying mechanism of action. PMID:23610573
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Lan, Yun-Feng; Zhang, Jian-Cheng; Gao, Jin-Lao; Wang, Xue-Ping; Fang, Zhou; Fu, Yi-Cheng; Chen, Mei-Yan; Lin, Min; Xue, Qiao; Li, Yang
2013-03-01
To investigate the effect of nerve growth factor (NGF) on the action potential and potassium currents of non-infarcted myocardium in the myocardial infarcted rabbit model. Rabbits with occlusion of the left anterior descending coronary artery were prepared and allowed to recover for eight weeks (healed myocardial infarction, HMI). During ligation surgery of the left coronary artery, a polyethylene tube was placed near the left stellate ganglion in the subcutis of the neck for the purpose of administering NGF 400 U/d for eight weeks (HMI + NGF group). Cardiomyocytes were isolated from regions of the non-infarcted left ventricular wall and the action potentials and ion currents in these cells were recorded using whole-cell patch clamps. Compared with HMI and control cardiomyocytes, significant prolongation of APD50 or APD90 (Action potential duration (APD) measured at 50% and 90% of repolarization) in HMI + NGF cardiomyocytes was found. The results showed that the 4-aminopyridine sensitive transient outward potassium current (I to), the rapidly activated omponent of delayed rectifier potassium current (I Kr), the slowly activated component of delayed rectifier potassium current (I Ks), and the L-type calcium current (I CaL) were significantly altered in NGF + HMI cardiomyocytes compared with HMI and control cells. Our results suggest that NGF treatment significantly prolongs APD in HMI cardiomyocytes and that a decrease in outward potassium currents and an increase of inward Ca(2+) current are likely the underlying mechanism of action.
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Song, Yejia; Belardinelli, Luiz
2017-12-14
Aging hearts have prolonged QT interval and are vulnerable to oxidative stress. Because the QT interval indirectly reflects the action potential duration (APD), we examined the hypotheses that 1) the APD of ventricular myocytes increases with age; 2) the age-related prolongation of APD is due to an enhancement of basal late Na + current (I NaL ); 3) inhibition of I NaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H 2 O 2 ). Experiments were performed on ventricular myocytes isolated from one-month (young) and one-year (old) guinea pigs (GPs). The APD of myocytes from old GPs was significantly longer than that from young GPs and was shortened by the I NaL inhibitors GS967 and tetrodotoxin. The magnitude of I NaL was significantly larger in myocytes from old than from young GPs. The CaMKII inhibitors KN-93 and AIP and the Na V 1.5-channel blocker MTSEA blocked the I NaL . There were no significant differences between myocytes from young and old GPs in L-type Ca 2+ current and the rapidly- and slowly-activating delayed rectifier K + currents, although the inward rectifier K + current was slightly decreased in myocytes from old GPs. H 2 O 2 induced more early afterdepolarizations in myocytes from old than from young GPs. The effect of H 2 O 2 was attenuated by GS967. The results suggest that 1) the APD of myocytes from old GPs is prolonged, 2) a CaMKII-mediated increase in Na V 1.5-channel I NaL is responsible for the prolongation of APD, and 3) Inhibition of I NaL may be beneficial for maintaining electrical stability under oxidative stress in myocytes of old GPs.
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Child, Nicholas; Hanson, Ben; Bishop, Martin; Rinaldi, Christopher A; Bostock, Julian; Western, David; Cooklin, Michael; O'Neil, Mark; Wright, Matthew; Razavi, Reza; Gill, Jaswinder; Taggart, Peter
2014-06-01
Mental stress and emotion have long been associated with ventricular arrhythmias and sudden death in animal models and humans. The effect of mental challenge on ventricular action potential duration (APD) in conscious healthy humans has not been reported. Activation recovery intervals measured from unipolar electrograms as a surrogate for APD (n=19) were recorded from right and left ventricular endocardium during steady-state pacing, whilst subjects watched an emotionally charged film clip. To assess the possible modulating role of altered respiration on APD, the subjects then repeated the same breathing pattern they had during the stress, but without the movie clip. Hemodynamic parameters (mean, systolic, and diastolic blood pressure, and rate of pressure increase) and respiration rate increased during the stressful part of the film clip (P=0.001). APD decreased during the stressful parts of the film clip, for example, for global right ventricular activation recovery interval at end of film clip 193.8 ms (SD, 14) versus 198.0 ms (SD, 13) during the matched breathing control (end film left ventricle 199.8 ms [SD, 16] versus control 201.6 ms [SD, 15]; P=0.004). Respiration rate increased during the stressful part of the film clip (by 2 breaths per minute) and was well matched in the respective control period without any hemodynamic or activation recovery interval changes. Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular APD in conscious humans. The effect of mental challenge on APD was not secondary to emotionally induced altered respiration or heart rate. © 2014 American Heart Association, Inc.
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Verduyn, S C; Vos, M A; Leunissen, H D; van Opstal, J M; Wellens, H J
1999-02-01
In the anesthetized dog with complete chronic AV block (CAVB), we evaluated and compared the acute electrophysiologic effects of dronedarone i.v. (Dron, 2 times 2.5 mg/kg/10 min) and amiodarone i.v. (Amio, 2 times 5 mg/kg/10 min). This canine model with a high sensitivity for acquired torsade de pointes (TdP) provides an ideal substrate to evaluate ventricular repolarization abnormalities. Six ECG leads and two endocardial monophasic action potential (MAP) recordings in the left and right ventricle (LV and RV) were simultaneously recorded to measure QT time, action-potential duration (APD), interventricular dispersion (deltaAPD = LV(APD) - RV(APD)), early afterdepolarizations (EADs), ectopic beats (EBs), and TdP. Measurements were made at the spontaneous idioventricular rhythm (IVR) and 1,000-ms steady-state pacing. To investigate its short-term, antiarrhythmic properties, Dron was given after almokalant (0.12 mg/kg)-induced TdP. Furthermore, in another set of experiments, oral Dron (20 mg/kg, b.i.d) was given for 3 weeks to conscious CAVB dogs. Dron, i.v., shortened ventricular repolarization (QT, 435 +/- 60 to 360 +/- 55; LV(APD) 395 +/- 75 to 335 +/- 60 ms; p < 0.05), whereas IVR and ventricular effective refractory period (VERP, 225 +/- 30 to 230 +/- 30 ms) remained similar. Therefore the VERP/QT ratio increased (0.55 +/- 0.04 to 0.61 +/- 0.03; p < 0.05). Similar results were obtained with Amio, i.v.. Almokalant-induced TdP was characterized by an increased repolarization duration, deltaAPD, and EADs. Dron, i.v., suppressed the EADs, EBs, and TdP by a reduction and homogenization of repolarization (LV(APD), 505 +/- 110 to 455 +/- 80 ms, and deltaAPD, 110 +/- 55 to 65 +/- 40 ms). Long-term oral Dron increased the PP interval, CL-IVR, and QT(c) time. In contrast to oral treatment, Dron i.v. shortens ventricular repolarization parameters, resulting in suppression of EAD-dependent acquired TdP. The increased VERP/QT ratio after Dron i.v. may indicate an important second antiarrhythmic property.
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Voigt, Niels; Heijman, Jordi; Trausch, Anne; Mintert-Jancke, Elisa; Pott, Lutz; Ravens, Ursula; Dobrev, Dobromir
2013-08-01
Shortened action-potential duration (APD) and blunted APD rate adaptation are hallmarks of chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K(+) currents (IK1 and IK,ACh, respectively) contribute to regulation of human atrial APD and are subject to cAF-dependent remodeling. Intracellular Na(+) ([Na(+)]i) enhances IK,ACh in experimental models but the effect of [Na(+)]i-dependent regulation of inward-rectifier K(+) currents on APD in human atrial myocytes is currently unknown. Here, we report a [Na(+)]i-dependent inhibition of outward IK1 in atrial myocytes from sinus rhythm (SR) or cAF patients. In contrast, IK,ACh activated by carbachol, a non-selective M-receptor agonist, increased with elevation of [Na(+)]i in SR. This [Na(+)]i-dependent IK,ACh regulation was absent in cAF. Including [Na(+)]i dependence of IK1 and IK,ACh in a recent computational model of the human atrial myocyte revealed that [Na(+)]i accumulation at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. [Na(+)]i-dependent IK,ACh augmentation at fast rates increased APD rate dependence in SR, but not in cAF. These results identify impaired Na(+)-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in patients with cAF. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Propagation of Electrical Excitation in a Ring of Cardiac Cells: A Computer Simulation Study
NASA Technical Reports Server (NTRS)
Kogan, B. Y.; Karplus, W. J.; Karpoukhin, M. G.; Roizen, I. M.; Chudin, E.; Qu, Z.
1996-01-01
The propagation of electrical excitation in a ring of cells described by the Noble, Beeler-Reuter (BR), Luo-Rudy I (LR I), and third-order simplified (TOS) mathematical models is studied using computer simulation. For each of the models it is shown that after transition from steady-state circulation to quasi-periodicity achieved by shortening the ring length (RL), the action potential duration (APD) restitution curve becomes a double-valued function and is located below the original ( that of an isolated cell) APD restitution curve. The distributions of APD and diastolic interval (DI) along a ring for the entire range of RL corresponding to quasi-periodic oscillations remain periodic with the period slightly different from two RLs. The 'S' shape of the original APD restitution curve determines the appearance of the second steady-state circulation region for short RLs. For all the models and the wide variety of their original APD restitution curves, no transition from quasi-periodicity to chaos was observed.
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Tur, Jared; Chapalamadugu, Kalyan C; Katnik, Christopher; Cuevas, Javier; Bhatnagar, Aruni; Tipparaju, Srinivas M
2017-03-01
The present study investigates the physiological role of Kvβ1 subunit for sensing pyridine nucleotide (NADH/NAD+) changes in the heart. We used Kvβ1.1 knockout (KO) or wild-type (WT) mice and established that Kvβ1.1 preferentially binds with Kv4.2 and senses the pyridine nucleotide changes in the heart. The cellular action potential duration (APD) obtained from WT cardiomyocytes showed longer APDs with lactate perfusion, which increases intracellular NADH levels, while the APDs remained unaltered in the Kvβ1.1 KO. Ex vivo monophasic action potentials showed a similar response, in which the APDs were prolonged in WT mouse hearts with lactate perfusion; however, the Kvβ1.1 KO mouse hearts did not show APD changes upon lactate perfusion. COS-7 cells coexpressing Kv4.2 and Kvβ1.1 were used for whole cell patch-clamp recordings to evaluate changes caused by NADH (lactate). These data reveal that Kvβ1.1 is required in the mediated inactivation of Kv4.2 currents, when NADH (lactate) levels are increased. In vivo, isoproterenol infusion led to increased NADH in the heart along with QTc prolongation in wild-type mice; regardless of the approach, our data show that Kvβ1.1 recognizes NADH changes and modulates Kv4.2 currents affecting AP and QTc durations. Overall, this study uses multiple levels of investigation, including the heterologous overexpression system, cardiomyocyte, ex vivo, and ECG, and clearly depicts that Kvβ1.1 is an obligatory sensor of NADH/NAD changes in vivo, with a physiological role in the heart. NEW & NOTEWORTHY Cardiac electrical activity is mediated by ion channels, and Kv4.2 plays a significant role, along with its binding partner, the Kvβ1.1 subunit. In the present study, we identify Kvβ1.1 as a sensor of pyridine nucleotide changes and as a modulator of Kv4.2 gating, action potential duration, and ECG in the mouse heart. Copyright © 2017 the American Physiological Society.
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Feng, Li; Gong, Jing; Jin, Zhen-yi; Li, Ning; Sun, Li-ping; Wu, Yi-ling; Pu, Jie-lin
2009-07-05
Shen song Yang xin (SSYX) is a compound of Chinese medicine with the effect of increasing heart rate (HR). This study aimed to evaluate its electrophysiological properties at heart and cellular levels. The Chinese miniature swines were randomly assigned to two groups, administered with SSYX or placebo for 4 weeks (n = 8 per group). Cardiac electrophysiological study (EPS) was performed before and after drug administration. The guinea pig ventricular myocytes were enzymatically isolated and whole cell voltage-clamp technique was used to evaluate the effect of SSYX on cardiac action potential (AP). SSYX treatment accelerated the HR from (141.8 +/- 36.0) beats per minute to (163.0 +/- 38.0) beats per minute (P = 0.013) without changing the other parameters in surface electrocardiogram. After blockage of the autonomic nervous system with metoprolol and atropin, SSYX had no effect on intrinsic HR (IHR), but decreased corrected sinus node recovery time (CSNRT) and sinus atrium conducting time (SACT). Intra cardiac EPS showed that SSYX significantly decreased the A-H and A-V intervals as well as shortened the atrial (A), atrioventricular node (AVN) and ventricular (V) effective refractory period (ERP). In isolated guinea pig ventricular myocytes, the most obvious effect of SSYX on action potential was a shortening of the action potential duration (APD) without change in shape of action potential. The shortening rates of APD(30), APD(50) and APD(90) were 19.5%, 17.8% and 15.3%, respectively. The resting potential (Em) and the interval between the end of APD(30) and APD(90) did not significantly change. The present study demonstrates that SSYX increases the HR and enhances the conducting capacity of the heart in the condition of the intact autonomic nervous system. SSYX homogenously decreases the ERP of the heart and shortens the APD of the myocytes, suggesting its antiarrhythmic effect without proarrhythmia.
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Zhang, X Q; Zhang, L Q; Palmer, B M; Ng, Y C; Musch, T I; Moore, R L; Cheung, J Y
2001-05-01
Two electrophysiological manifestations of myocardial infarction (MI)-induced myocyte hypertrophy are prolongation of action potential duration (APD) and reduction of transient outward current (I(to)) density. Because high-intensity sprint training (HIST) ameliorated myocyte hypertrophy and improved myocyte Ca(2+) homeostasis and contractility after MI, the present study evaluated whether 6-8 wk of HIST would shorten the prolonged APD and improve the depressed I(to) in post-MI myocytes. There were no differences in resting membrane potential and action potential amplitude (APA) measured in myocytes isolated from sham-sedentary (Sed), MI-Sed, and MI-HIST groups. Times required for repolarization to 50 and 90% APA were significantly (P < 0.001) prolonged in MI-Sed myocytes. HIST reduced times required for repolarization to 50 and 90% APA to values observed in Sham-Sed myocytes. The fast and slow components of I(to) were significantly (P < 0.0001) reduced in MI-Sed myocytes. HIST significantly (P < 0.001) enhanced the fast and slow components of I(to) in MI myocytes, although not to levels observed in Sham-Sed myocytes. There were no significant differences in steady-state I(to) inactivation and activation parameters among Sham-Sed, MI-Sed, and MI-HIST myocytes. Likewise, recovery from time-dependent inactivation was also similar among the three groups. We suggest that normalization of APD after MI by HIST may be mediated by restoration of I(to) toward normal levels.
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Broux, B; De Clercq, D; Decloedt, A; Van Der Vekens, N; Verheyen, T; Ven, S; Pardon, B; van Loon, G
2016-07-01
The electrocardiographic differentiation between atrial (APDs) and ventricular (VPDs) premature depolarizations is important. P wave prematurity and normal QRS and T wave morphology generally are used as discriminating criteria for APDs. The aim of this study was to determine whether P, Q, R, S, and T wave amplitude, PQ interval, QRS and P wave duration and P and T wave morphology differ between APDs and sinus beats. To determine the relationship between the RR coupling interval and the change in S wave amplitude between sinus beats and APDs. Case-control study. From a modified base-apex configuration of 30 horses with APDs at rest, sinus beat and APD associated preceding RR interval, P, PQ and QRS duration and P, R, S, and T wave amplitudes were measured. Linear mixed models and logistic regression were used to determine the effect of APDs on the ECG variables studied. In comparison to sinus beats, APDs were associated with a significant (P < .001) change in P amplitude (-0.03 ± 0.01 mV) and increase in S (0.20 ± 0.02 mV) and T (0.08 ± 0.03 mV) amplitude. PQ (-20.3 ± 5.2 ms) and RR (-519 ± 14 ms) interval and P duration (-21.1 ± 3.0 ms) decreased (P < .001). APDs were significantly associated with a singular positive P wave (OR: 11.0, P < .001) and were more likely to have a monophasic positive T wave (OR: 9.2, P < .001). A smaller RR coupling interval was associated with an increased relative difference in S amplitude (P < .01). Atrial premature depolarizations may lead to changes in QRS and T wave morphology. Knowledge of these changes is important to avoid interpreting certain APDs as VPDs. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.
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Decker, Keith F; Heijman, Jordi; Silva, Jonathan R; Hund, Thomas J; Rudy, Yoram
2009-04-01
Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current (I(to1)), the slow component of the delayed rectifier K(+) current (I(Ks)), the L-type Ca(2+) channel current (I(Ca,L)), and the Na(+)-K(+) pump current (I(NaK)) fit to data from canine ventricular myocytes. We found that I(to1) plays a limited role in potentiating peak I(Ca,L) and sarcoplasmic reticulum Ca(2+) release for propagated APs but modulates the time course of APD restitution. I(Ks) plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that I(Ca,L) plays a critical role in APD accommodation and rate dependence of APD restitution. Ca(2+) entry via I(Ca,L) at fast rate drives increased Na(+)-Ca(2+) exchanger Ca(2+) extrusion and Na(+) entry, which in turn increases Na(+) extrusion via outward I(NaK). APD accommodation results from this increased outward I(NaK). Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets.
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Heart rate variability alters cardiac repolarization and electromechanical dynamics.
Phadumdeo, Vrishti M; Weinberg, Seth H
2018-04-07
Heart rate continuously varies due to autonomic regulation, stochasticity in pacemaking, and circadian rhythm, collectively termed heart rate variability (HRV), during normal physiological conditions. Low HRV is clinically associated with an elevated risk of cardiac arrhythmias. Alternans, a beat-to-beat alternation in action potential duration (APD) and/or intracellular calcium (Ca) transient, is a well-known risk factor associated with cardiac arrhythmias that is typically studied under conditions of a constant pacing rate, i.e., the absence of HRV. In this study, we investigate the effects of HRV on the interplay between APD, Ca, and electromechanical properties, employing a nonlinear discrete-time map model that governs APD and intracellular Ca cycling with a stochastic pacing period. We find that HRV can decrease variation in APD and peak Ca at fast pacing rates for which alternans is present. Further, increased HRV typically disrupts the alternating pattern for both APD and peak Ca and weakens the correlation between APD and peak Ca, thus decoupling Ca-mediated instabilities from repolarization alternation. We find that the efficacy of these effects is regulated by the sarcoplasmic reticulum Ca uptake rate. Overall, these results demonstrate that HRV disrupts arrhythmogenic alternans and suggests that HRV may be a significant factor in preventing life-threatening arrhythmias. Copyright © 2018 Elsevier Ltd. All rights reserved.
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The transfer functions of cardiac tissue during stochastic pacing.
de Lange, Enno; Kucera, Jan P
2009-01-01
The restitution properties of cardiac action potential duration (APD) and conduction velocity (CV) are important factors in arrhythmogenesis. They determine alternans, wavebreak, and the patterns of reentrant arrhythmias. We developed a novel approach to characterize restitution using transfer functions. Transfer functions relate an input and an output quantity in terms of gain and phase shift in the complex frequency domain. We derived an analytical expression for the transfer function of interbeat intervals (IBIs) during conduction from one site (input) to another site downstream (output). Transfer functions can be efficiently obtained using a stochastic pacing protocol. Using simulations of conduction and extracellular mapping of strands of neonatal rat ventricular myocytes, we show that transfer functions permit the quantification of APD and CV restitution slopes when it is difficult to measure APD directly. We find that the normally positive CV restitution slope attenuates IBI variations. In contrast, a negative CV restitution slope (induced by decreasing extracellular [K(+)]) amplifies IBI variations with a maximum at the frequency of alternans. Hence, it potentiates alternans and renders conduction unstable, even in the absence of APD restitution. Thus, stochastic pacing and transfer function analysis represent a powerful strategy to evaluate restitution and the stability of conduction.
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Qu, Z; Kil, J; Xie, F; Garfinkel, A; Weiss, J N
2000-01-01
Scroll wave (vortex) breakup is hypothesized to underlie ventricular fibrillation, the leading cause of sudden cardiac death. We simulated scroll wave behaviors in a three-dimensional cardiac tissue model, using phase I of the Luo-Rudy (LR1) action potential model. The effects of action potential duration (APD) restitution, tissue thickness, filament twist, and fiber rotation were studied. We found that APD restitution is the major determinant of scroll wave behavior and that instabilities arising from APD restitution are the main determinants of scroll wave breakup in this cardiac model. We did not see a "thickness-induced instability" in the LR1 model, but a minimum thickness is required for scroll breakup in the presence of fiber rotation. The major effect of fiber rotation is to maintain twist in a scroll wave, promoting filament bending and thus scroll breakup. In addition, fiber rotation induces curvature in the scroll wave, which weakens conduction and further facilitates wave break. PMID:10827961
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Slow adaptation of ventricular repolarization as a cause of arrhythmia?
Bueno-Orovio, A; Hanson, B M; Gill, J S; Taggart, P; Rodriguez, B
2014-01-01
This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Advanced Methods for Studying Cardiovascular and Respiratory Systems". Adaptation of the QT-interval to changes in heart rate reflects on the body-surface electrocardiogram the adaptation of action potential duration (APD) at the cellular level. The initial fast phase of APD adaptation has been shown to modulate the arrhythmia substrate. Whether the slow phase is potentially proarrhythmic remains unclear. To analyze in-vivo human data and use computer simulations to examine effects of the slow APD adaptation phase on dispersion of repolarization and reentry in the human ventricle. Electrograms were acquired from 10 left and 10 right ventricle (LV/RV) endocardial sites in 15 patients with normal ventricles during RV pacing. Activation-recovery intervals, as a surrogate for APD, were measured during a sustained increase in heart rate. Observed dynamics were studied using computer simulations of human tissue electrophysiology. Spatial heterogeneity of rate adaptation was observed in all patients. Inhomogeneity in slow APD adaptation time constants (Δτ(s)) was greater in LV than RV (Δτ(s)(LV) = 31.8 ± 13.2, Δτ(s)(RV) = 19.0 ± 12.8 s , P< 0.01). Simulations showed that altering local slow time constants of adaptation was sufficient to convert partial wavefront block to block with successful reentry. Using electrophysiological data acquired in-vivo in human and computer simulations, we identify heterogeneity in the slow phase of APD adaptation as an important component of arrhythmogenesis.
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Saxena, P; Hortigon‐Vinagre, M P; Beyl, S; Baburin, I; Andranovits, S; Iqbal, S M; Costa, A; IJzerman, A P; Kügler, P; Timin, E
2017-01-01
Background and Purpose Human ether‐a‐go‐go‐related gene (hERG; Kv11.1) channel inhibition is a widely accepted predictor of cardiac arrhythmia. hERG channel inhibition alone is often insufficient to predict pro‐arrhythmic drug effects. This study used a library of dofetilide derivatives to investigate the relationship between standard measures of hERG current block in an expression system and changes in action potential duration (APD) in human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs). The interference from accompanying block of Cav1.2 and Nav1.5 channels was investigated along with an in silico AP model. Experimental Approach Drug‐induced changes in APD were assessed in hiPSC‐CMs using voltage‐sensitive dyes. The IC50 values for dofetilide and 13 derivatives on hERG current were estimated in an HEK293 expression system. The relative potency of each drug on APD was estimated by calculating the dose (D150) required to prolong the APD at 90% (APD90) repolarization by 50%. Key Results The D150 in hiPSC‐CMs was linearly correlated with IC50 of hERG current. In silico simulations supported this finding. Three derivatives inhibited hERG without prolonging APD, and these compounds also inhibited Cav1.2 and/or Nav1.5 in a channel state‐dependent manner. Adding Cav1.2 and Nav1.2 block to the in silico model recapitulated the direction but not the extent of the APD change. Conclusions and Implications Potency of hERG current inhibition correlates linearly with an index of APD in hiPSC‐CMs. The compounds that do not correlate have additional effects including concomitant block of Cav1.2 and/or Nav1.5 channels. In silico simulations of hiPSC‐CMs APs confirm the principle of the multiple ion channel effects. PMID:28681507
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Qiu, Xiaoliang S; Chauveau, Samuel; Anyukhovsky, Evgeny P; Rahim, Tania; Jiang, Ya-Ping; Harleton, Erin; Feinmark, Steven J; Lin, Richard Z; Coronel, Ruben; Janse, Michiel J; Opthof, Tobias; Rosen, Tove S; Cohen, Ira S; Rosen, Michael R
2016-04-01
Drugs are screened for delayed rectifier potassium current (IKr) blockade to predict long QT syndrome prolongation and arrhythmogenesis. However, single-cell studies have shown that chronic (hours) exposure to some IKr blockers (eg, dofetilide) prolongs repolarization additionally by increasing late sodium current (INa-L) via inhibition of phosphoinositide 3-kinase. We hypothesized that chronic dofetilide administration to intact dogs prolongs repolarization by blocking IKr and increasing INa-L. We continuously infused dofetilide (6-9 μg/kg bolus+6-9 μg/kg per hour IV infusion) into anesthetized dogs for 7 hours, maintaining plasma levels within the therapeutic range. In separate experiments, myocardial biopsies were taken before and during 6-hour intravenous dofetide infusion, and the level of phospho-Akt was determined. Acute and chronic dofetilide effects on action potential duration (APD) were studied in canine left ventricular subendocardial slabs using microelectrode techniques. Dofetilide monotonically increased QTc and APD throughout 6.5-hour exposure. Dofetilide infusion during ≥210 minutes inhibited Akt phosphorylation. INa-L block with lidocaine shortened QTc and APD more at 6.5 hours than at 50 minutes (QTc) or 30 minutes (APD) dofetilide administration. In comparison, moxifloxacin, an IKr blocker with no effects on phosphoinositide 3-kinase and INa-L prolonged APD acutely but no additional prolongation occurred on chronic superfusion. Lidocaine shortened APD equally during acute and chronic moxifloxacin superfusion. Increased INa-L contributes to chronic dofetilide effects in vivo. These data emphasize the need to include time and INa-L in evaluating the phosphoinositide 3-kinase inhibition-derived proarrhythmic potential of drugs and provide a mechanism for benefit from lidocaine administration in clinical acquired long QT syndrome. © 2016 American Heart Association, Inc.
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2018-01-01
Electrical restitution (ER) is a major determinant of repolarization stability and, under fast pacing rate, it reveals memory properties of the cardiac action potential (AP), whose dynamics have never been fully elucidated, nor their ionic mechanisms. Previous studies have looked at ER mainly in terms of changes in AP duration (APD) when the preceding diastolic interval (DI) changes and described dynamic conditions where this relationship shows hysteresis which, in turn, has been proposed as a marker of short-term AP memory and repolarization stability. By means of numerical simulations of a non-propagated human ventricular AP, we show here that measuring ER as APD versus the preceding cycle length (CL) provides additional information on repolarization dynamics which is not contained in the companion formulation. We focus particularly on fast pacing rate conditions with a beat-to-beat variable CL, where memory properties emerge from APD vs CL and not from APD vs DI and should thus be stored in APD and not in DI. We provide an ion-currents characterization of such conditions under periodic and random CL variability, and show that the memory stored in APD plays a stabilizing role on AP repolarization under pacing rate perturbations. The gating kinetics of L-type calcium current seems to be the main determinant of this safety mechanism. We also show that, at fast pacing rate and under otherwise identical pacing conditions, a periodically beat-to-beat changing CL is more effective than a random one in stabilizing repolarization. In summary, we propose a novel view of short-term AP memory, differentially stored between systole and diastole, which opens a number of methodological and theoretical implications for the understanding of arrhythmia development. PMID:29494628
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Uzelac, Ilija; Ji, Yanyan C.; Hornung, Daniel; Schröder-Scheteling, Johannes; Luther, Stefan; Gray, Richard A.; Cherry, Elizabeth M.; Fenton, Flavio H.
2017-01-01
Rationale: Discordant alternans, a phenomenon in which the action potential duration (APDs) and/or intracellular calcium transient durations (CaDs) in different spatial regions of cardiac tissue are out of phase, present a dynamical instability for complex spatial dispersion that can be associated with long-QT syndrome (LQTS) and the initiation of reentrant arrhythmias. Because the use of numerical simulations to investigate arrhythmic effects, such as acquired LQTS by drugs is beginning to be studied by the FDA, it is crucial to validate mathematical models that may be used during this process. Objective: In this study, we characterized with high spatio-temporal resolution the development of discordant alternans patterns in transmembrane voltage (Vm) and intracellular calcium concentration ([Cai]+2) as a function of pacing period in rabbit hearts. Then we compared the dynamics to that of the latest state-of-the-art model for ventricular action potentials and calcium transients to better understand the underlying mechanisms of discordant alternans and compared the experimental data to the mathematical models representing Vm and [Cai]+2 dynamics. Methods and Results: We performed simultaneous dual optical mapping imaging of Vm and [Cai]+2 in Langendorff-perfused rabbit hearts with higher spatial resolutions compared with previous studies. The rabbit hearts developed discordant alternans through decreased pacing period protocols and we quantified the presence of multiple nodal points along the direction of wave propagation, both in APD and CaD, and compared these findings with results from theoretical models. In experiments, the nodal lines of CaD alternans have a steeper slope than those of APD alternans, but not as steep as predicted by numerical simulations in rabbit models. We further quantified several additional discrepancies between models and experiments. Conclusions: Alternans in CaD have nodal lines that are about an order of magnitude steeper compared to those of APD alternans. Current action potential models lack the necessary coupling between voltage and calcium compared to experiments and fail to reproduce some key dynamics such as, voltage amplitude alternans, smooth development of calcium alternans in time, conduction velocity and the steepness of the nodal lines of APD and CaD. PMID:29104543
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Lu, H R; Hortigon-Vinagre, M P; Zamora, V; Kopljar, I; De Bondt, A; Gallacher, D J; Smith, G
2017-09-01
Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. Here, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10kHz and the records subsequently analyzed off-line. Cells were exposed to 30min incubation to vehicle or compound (n=5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (T rise ) of the optical action potential duration (oAPD). Significant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with I Ca -antagonists, I Kr -activator or ATP-sensitive K + channel (K ATP )-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. The results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase. Copyright © 2017 Elsevier Inc. All rights reserved.
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Flecainide attenuates rate adaptation of ventricular repolarization in guinea-pig heart.
Osadchii, Oleg E
2016-01-01
Flecainide is class Ic antiarrhythmic agent that was found to increase the risk of sudden cardiac death. Arrhythmic responses to flecainide could be precipitated by exercise, suggesting a role played by inappropriate rate adaptation of ventricular repolarization. This study therefore examined flecainide effect on adaptation of the QT interval and ventricular action potential duration (APD) to abrupt reductions of the cardiac cycle length. ECG and ventricular epicardial and endocardial monophasic APD were recorded in isolated, perfused guinea-pig heart preparations upon a sustained cardiac acceleration (rapid pacing for 30 s), and following a single perturbation of the cycle length evoked by extrasystolic stimulation. Sustained increase in heart rate was associated with progressive bi-exponential shortening of the QT interval and APD. Flecainide prolonged ventricular repolarization, delayed its rate adaptation, and decreased the amplitude of QT interval and APD shortening upon rapid cardiac pacing. During extrasystolic stimulation, flecainide attenuated APD shortening in premature ventricular beats, with effect being greater upon using a longer basic drive cycle length (S1-S1=550 ms versus S1-S1=300 ms). Flecainide-induced arrhythmia may be partly accounted for by attenuated adaptation of ventricular repolarization to sudden changes in cardiac cycle length provoked by transient tachycardia or ectopic beats.
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Walton, Richard D.; Benson, Alan P.; Hardy, Matthew E. L.; White, Ed; Bernus, Olivier
2013-01-01
Spatial dispersion of repolarization is known to play an important role in arrhythmogenesis. Electrotonic modulation of repolarization by the activation sequence has been observed in some species and tissue preparations, but to varying extents. Our study sought to determine the mechanisms underlying species- and tissue-dependent electrotonic modulation of repolarization in ventricles. Epi-fluorescence optical imaging of whole rat hearts and pig left ventricular wedges were used to assess epicardial spatial activation and repolarization characteristics. Experiments were supported by computer simulations using realistic geometries. Tight coupling between activation times (AT) and action potential duration (APD) were observed in rat experiments but not in pig. Linear correlation analysis found slopes of −1.03 ± 0.59 and −0.26 ± 0.13 for rat and pig, respectively (p < 0.0001). In rat, maximal dispersion of APD was 11.0 ± 3.1 ms but dispersion of repolarization time (RT) was relatively homogeneous (8.2 ± 2.7, p < 0.0001). However, in pig no such difference was observed between the dispersion of APD and RT (17.8 ± 6.1 vs. 17.7 ± 6.5, respectively). Localized elevations of APD (12.9 ± 8.3%) were identified at ventricular insertion sites of rat hearts both in experiments and simulations. Tissue geometry and action potential (AP) morphology contributed significantly to determining influence of electrotonic modulation. Simulations of a rat AP in a pig geometry decreased the slope of AT and APD relationships by 70.6% whereas slopes were increased by 75.0% when implementing a pig AP in a rat geometry. A modified pig AP, shortened to match the rat APD, showed little coupling between AT and APD with greatly reduced slope compared to the rat AP. Electrotonic modulation of repolarization by the activation sequence is especially pronounced in small hearts with murine-like APs. Tissue architecture and AP morphology play an important role in electrotonic modulation of repolarization. PMID:24115934
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Ahmmed, G U; Dong, P H; Song, G; Ball, N A; Xu, Y; Walsh, R A; Chiamvimonvat, N
2000-03-17
Ventricular arrhythmias are common in both cardiac hypertrophy and failure; cardiac failure in particular is associated with a significant increase in the risk of sudden cardiac death. We studied the electrophysiologic changes in a guinea pig model with aortic banding resulting in cardiac hypertrophy at 4 weeks and progressing to cardiac failure at 8 weeks using whole-cell patch-clamp and biochemical techniques. Action potential durations (APDs) were significantly prolonged in banded animals at 4 and 8 weeks compared with age-matched sham-operated animals. APDs at 50% and 90% repolarization (APD(50) and APD(90) in ms) were the following: 4 week, banded, 208+/-51 and 248+/-49 (n = 15); 4 week, sham, 189+/-68 and 213+/-69 (n = 16); 8 week, banded, 197+/-40 and 226+/-40 (n = 21); and 8 week, sham, 156+/-42 and 189+/-45 (n = 22), respectively; P<0.05 comparing banded versus sham-operated animals. We observed no significant differences in the K(+) currents between the 2 groups of animals at 4 and 8 weeks. However, banded animals exhibited a significant increase in Na(+) and Na(+)-Ca(2+) exchange current densities compared with controls. Furthermore, we have found a significant attenuation in the Ca(2+)-dependent inactivation of the L-type Ca(2+) current in the banded compared with sham-operated animals, likely as a result of the significant downregulation of the sarcoplasmic reticulum Ca(2+) ATPase, which has been documented previously in the heart failure animals. Our data provide an alternate mechanism for APD prolongation in cardiac hypertrophy and failure and support the notion that there is close interaction between Ca(2+) handling and action potential profile.
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Porter, Bradley; van Duijvenboden, Stefan; Bishop, Martin J.; Orini, Michele; Claridge, Simon; Gould, Justin; Sieniewicz, Benjamin J.; Sidhu, Baldeep; Razavi, Reza; Rinaldi, Christopher A.; Gill, Jaswinder S.; Taggart, Peter
2018-01-01
Background: The temporal pattern of ventricular repolarization is of critical importance in arrhythmogenesis. Enhanced beat-to-beat variability (BBV) of ventricular action potential duration (APD) is pro-arrhythmic and is increased during sympathetic provocation. Since sympathetic nerve activity characteristically exhibits burst patterning in the low frequency range, we hypothesized that physiologically enhanced sympathetic activity may not only increase BBV of left ventricular APD but also impose a low frequency oscillation which further increases repolarization instability in humans. Methods and Results: Heart failure patients with cardiac resynchronization therapy defibrillator devices (n = 11) had activation recovery intervals (ARI, surrogate for APD) recorded from left ventricular epicardial electrodes alongside simultaneous non-invasive blood pressure and respiratory recordings. Fixed cycle length was achieved by right ventricular pacing. Recordings took place during resting conditions and following an autonomic stimulus (Valsalva). The variability of ARI and the normalized variability of ARI showed significant increases post Valsalva when compared to control (p = 0.019 and p = 0.032, respectively). The oscillatory behavior was quantified by spectral analysis. Significant increases in low frequency (LF) power (p = 0.002) and normalized LF power (p = 0.019) of ARI were seen following Valsalva. The Valsalva did not induce changes in conduction variability nor the LF oscillatory behavior of conduction. However, increases in the LF power of ARI were accompanied by increases in the LF power of systolic blood pressure (SBP) and the rate of systolic pressure increase (dP/dtmax). Positive correlations were found between LF-SBP and LF-dP/dtmax (rs = 0.933, p < 0.001), LF-ARI and LF-SBP (rs = 0.681, p = 0.001) and between LF-ARI and LF-dP/dtmax (rs = 0.623, p = 0.004). There was a strong positive correlation between the variability of ARI and LF power of ARI (rs = 0.679, p < 0.001). Conclusions: In heart failure patients, physiological sympathetic provocation induced low frequency oscillation (~0.1 Hz) of left ventricular APD with a strong positive correlation between the LF power of APD and the BBV of APD. These findings may be of importance in mechanisms underlying stability/instability of repolarization and arrhythmogenesis in humans. PMID:29670531
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Theory of the development of alternans in the heart during controlled diastolic interval pacing
NASA Astrophysics Data System (ADS)
Otani, Niels F.
2017-09-01
The beat-to-beat alternation in action potential durations (APDs) in the heart, called APD alternans, has been linked to the development of serious cardiac rhythm disorders, including ventricular tachycardia and fibrillation. The length of the period between action potentials, called the diastolic interval (DI), is a key dynamical variable in the standard theory of alternans development. Thus, methods that control the DI may be useful in preventing dangerous cardiac rhythms. In this study, we examine the dynamics of alternans during controlled-DI pacing using a series of single-cell and one-dimensional (1D) fiber models of alternans dynamics. We find that a model that combines a so-called memory model with a calcium cycling model can reasonably explain two key experimental results: the possibility of alternans during constant-DI pacing and the phase lag of APDs behind DIs during sinusoidal-DI pacing. We also find that these results can be replicated by incorporating the memory model into an amplitude equation description of a 1D fiber. The 1D fiber result is potentially concerning because it seems to suggest that constant-DI control of alternans can only be effective over only a limited region in space.
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O’Connell, Ryan P.; Musa, Hassan; Gomez, Mario San Martin; Avula, Uma Mahesh; Herron, Todd J.; Kalifa, Jerome; Anumonwo, Justus M. B.
2015-01-01
Background Epicardial adiposity and plasma levels of free fatty acids (FFAs) are elevated in atrial fibrillation, heart failure and obesity, with potentially detrimental effects on myocardial function. As major components of epicardial fat, FFAs may be abnormally regulated, with a potential to detrimentally modulate electro-mechanical function. The cellular mechanisms underlying such effects of FFAs are unknown. Objective To determine the mechanisms underlying electrophysiological effects of palmitic (PA), stearic (SA) and oleic (OA) FFAs on sheep atrial myocytes. Methods We used electrophysiological techniques, numerical simulations, biochemistry and optical imaging to examine the effects of acutely (≤ 15 min), short-term (4–6 hour) or 24-hour application of individual FFAs (10 μM) on isolated ovine left atrial myocytes (LAMs). Results Acute and short-term incubation in FFAs resulted in no differences in passive or active properties of isolated left atrial myocytes (LAMs). 24-hour application had differential effects depending on the FFA. PA did not affect cellular passive properties but shortened (p<0.05) action potential duration at 30% repolarization (APD30). APD50 and APD80 were unchanged. SA had no effect on resting membrane potential but reduced membrane capacitance by 15% (p<0.05), and abbreviated APD at all values measured (p≤0.001). OA did not significantly affect passive or active properties of LAMs. Measurement of the major voltage-gated ion channels in SA treated LAMs showed a ~60% reduction (p<0.01) of the L-type calcium current (ICa-L) and ~30% reduction (p<0.05) in the transient outward potassium current (ITO). A human atrial cell model recapitulated SA effects on APD. Optical imaging showed that SA incubated for 24 hours altered t-tubular structure in isolated cells (p<0.0001). Conclusions SA disrupts t-tubular architecture and remodels properties of membrane ionic currents in sheep atrial myocytes, with potential implications in arrhythmogenesis. PMID:26274906
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O'Connell, Ryan P; Musa, Hassan; Gomez, Mario San Martin; Avula, Uma Mahesh; Herron, Todd J; Kalifa, Jerome; Anumonwo, Justus M B
2015-01-01
Epicardial adiposity and plasma levels of free fatty acids (FFAs) are elevated in atrial fibrillation, heart failure and obesity, with potentially detrimental effects on myocardial function. As major components of epicardial fat, FFAs may be abnormally regulated, with a potential to detrimentally modulate electro-mechanical function. The cellular mechanisms underlying such effects of FFAs are unknown. To determine the mechanisms underlying electrophysiological effects of palmitic (PA), stearic (SA) and oleic (OA) FFAs on sheep atrial myocytes. We used electrophysiological techniques, numerical simulations, biochemistry and optical imaging to examine the effects of acutely (≤ 15 min), short-term (4-6 hour) or 24-hour application of individual FFAs (10 μM) on isolated ovine left atrial myocytes (LAMs). Acute and short-term incubation in FFAs resulted in no differences in passive or active properties of isolated left atrial myocytes (LAMs). 24-hour application had differential effects depending on the FFA. PA did not affect cellular passive properties but shortened (p<0.05) action potential duration at 30% repolarization (APD30). APD50 and APD80 were unchanged. SA had no effect on resting membrane potential but reduced membrane capacitance by 15% (p<0.05), and abbreviated APD at all values measured (p≤0.001). OA did not significantly affect passive or active properties of LAMs. Measurement of the major voltage-gated ion channels in SA treated LAMs showed a ~60% reduction (p<0.01) of the L-type calcium current (ICa-L) and ~30% reduction (p<0.05) in the transient outward potassium current (ITO). A human atrial cell model recapitulated SA effects on APD. Optical imaging showed that SA incubated for 24 hours altered t-tubular structure in isolated cells (p<0.0001). SA disrupts t-tubular architecture and remodels properties of membrane ionic currents in sheep atrial myocytes, with potential implications in arrhythmogenesis.
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Zhao, Zhenying; Yin, Yongqiang; Wu, Hong; Jiang, Min; Lou, Jianshi; Bai, Gang; Luo, Guo'an
2013-01-01
Arctigenin possesses biological activities, but its underlying mechanisms at the cellular and ion channel levels are not completely understood. Therefore, the present study was designed to identify the anti-arrhythmia effect of arctigenin in vivo, as well as its cellular targets and mechanisms. A rat arrhythmia model was established via continuous aconitine infusion, and the onset times of ventricular premature contraction, ventricular tachycardia and death were recorded. The Action Potential Duration (APD), sodium current (I(Na)), L-type calcium current (I(Ca, L)) and transient outward potassium current (I(to)) were measured and analysed using a patch-clamp recording technique in normal rat cardiomyocytes and myocytes of arrhythmia aconitine-induced by. Arctigenin significantly delayed the arrhythmia onset in the aconitine-induced rat model. The 50% and 90% repolarisations (APD50 and APD90) were shortened by 100 µM arctigenin; the arctigenin dose also inhibited the prolongation of APD50 and APD90 caused by 1 µM aconitine. Arctigenin inhibited I(Na) and I(Ca,L) and attenuated the aconitine-increased I(Na) and I(Ca,L) by accelerating the activation process and delaying the inactivation process. Arctigenin enhanced Ito by facilitating the activation process and delaying the inactivation process, and recoverd the decreased Ito induced by aconitine. Arctigenin has displayed anti-arrhythmia effects, both in vivo and in vitro. In the context of electrophysiology, I(Na), I(Ca, L), and I(to) may be multiple targets of arctigenin, leading to its antiarrhythmic effect. © 2013 S. Karger AG, Basel.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Yang, Baode; Li, Chenxing
Excessive consumption of alcohol is a well-established risk factor of atrial fibrillation (AF). However, the effects of moderate alcohol drinking remain to be elucidated. This study was designed to determine the effects of moderate ethanol ingestion on atrial fibrillation and the electrophysiological mechanisms. In acetylcholine-induced canine and mouse AF models, the moderate ethanol prevented the generation and persistence of AF through prolonging the latent period of AF and shortening the duration of AF. The action potential duration (APD) was remarkably prolonged under the concentration range of 12.5–50.0 mM ethanol in guinea pig atrial myocytes. Ultra-rapid delayed rectified potassium currents (I{submore » Kv1.5}) were markedly inhibited by 12.5–50.0 mM ethanol in a concentration-dependent manner. Ethanol with 50.0 mM could inhibit rapid delayed rectifier potassium currents (I{sub hERG}). Ethanol under 6.25–50.0 mM did not affect on inward rectifier potassium currents (I{sub Kir2.1}). Collectively, the present study provided an evidence that moderate ethanol intake can prolong the APD of atrial myocytes by inhibition of I{sub Kv1.5} and I{sub hERG}, which contributed to preventing the development and duration of AF. - Highlights: • Moderate ethanol prevented the development of AF in animal models. • Moderate ethanol prolonged APD in guinea pig atrial myocytes. • Moderate ethanol inhibited Kv1.5 currents.« less
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Arteyeva, Natalia V; Azarov, Jan E
2017-01-01
The changes in ventricular repolarization gradients lead to significant alterations of the electrocardiographic body surface T waves up to the T wave inversion. However, the contribution of a specific gradient remains to be elucidated. The objective of the present investigation was to study the role of the transmural repolarization gradient in the inversion of the body surface T wave with a mathematical model of the hypothermia-induced changes of ventricular repolarization. By means of mathematical simulation, we set the hypothermic action potential duration (APD) distribution on the rabbit ventricular epicardium as it was previously experimentally documented. Then the parameters of the body surface potential distribution were tested with the introduction of different scenarios of the endocardial and epicardial APD behavior in hypothermia resulting in the unchanged, reversed or enlarged transmural repolarization gradient. The reversal of epicardial repolarization gradients (apicobasal, anterior-posterior and interventricular) caused the inversion of the T waves regardless of the direction of the transmural repolarization gradient. However, the most realistic body surface potentials were obtained when the endocardial APDs were not changed under hypothermia while the epicardial APDs prolonged. This produced the reversed and increased transmural repolarization gradient in absolute magnitude. The body surface potentials simulated under the unchanged transmural gradient were reduced in comparison to those simulated under the reversed transmural gradient. The simulations demonstrated that the transmural repolarization gradient did not play a crucial role in the cardiac electric field inversion under hypothermia, but its magnitude and direction contribute to the T wave amplitude. © 2016 Wiley Periodicals, Inc.
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Pustovit, K B; Kuz'min, V S; Sukhova, G S
2014-04-01
This study is aimed to the investigation of the nicotinamide adenine dinucleotide (NAD+) effects and mechanisms of action in a heart. NAD+ (mcM) induces multiphase alternation of contractile activity of isolated rat heart: short positive inotropic action is followed by a negative inotropic phase. NAD+ (1-100 mcM) induces decreasing of action potential duration (APD) in rat atrial myocardium (from 45 +/- 0.82 ms in control experiments to 39 +/- 1.05 (n = 8) and 32 +/- 2 (n = 8) during application of 10 and 100 mcM of NAD+, respectively). Significant APD increase (from 45 +/- 0.82 ms to 74 +/- 1.89 (n = 8) ms) was observed during washing out of NAD+ (100 mcM). ATP or adenosine was unable to increase APD both during application or washing out. NAD+ induced APD decrease was not suppressed by P1-antagonist theophylline. P1-purinoreceptor and metabolite independent direct action of NAD+ in rat heart is suggested. Activation of P2X or P2Y receptors, cyclic ADP-ribose accumulation in cardiomyocytes is proposed as a main mechanism of NAD(+)-induced effects in the heart.
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Chang, Po-Cheng; Lu, Yu-Ying; Lee, Hui-Ling; Lin, Shien-Fong; Chu, Yen; Wen, Ming-Shien; Chou, Chung-Chuan
2018-05-03
Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium-calcium exchanger (NCX) inhibition in genesis secondary Ca rise and EADs-TdP is still debated. Dual voltage and intracellular Ca optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development. E4031 enhanced secondary Ca rise, EADs development and TdP inducibility in both control and failing hearts. The results showed that ORM-10103 reduced premature ventricular beats (PVBs) but was unable to suppress the inducibility of TdP or EADs. The electrophysiological effects of ORM-10103 included prolongation of action potential duration (APD) and increased APD heterogeneity in failing hearts. ORM10103 had a neutral effect on the amplitude of secondary Cai rise in control and HF groups. In this model, most EADs generated from the long-short APD junction area. In conclusion, highly selective NCX inhibition with ORM-10103 reduced PVB burden but was unable to suppress secondary Ca rise, EADs development nor inducibility of TdP. The possible electrophysiological mechanisms include APD prolongation and increased APD heterogeneity.
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Fukuda, Hitoshi; Morita, Yukie; Shiotani, Norio; Mizuo, Midori; Komae, Norihisa
2004-08-01
The potential for QT interval prolongation of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, was investigated by in vitro and in vivo electrophysiology studies. Following results were obtained. In vitro electrophysiology study using guinea pig papillary muscles: PZFX mesilate (30-300 microM) had no effects on resting membrane potential (RMP), action potential amplitude (APA) and action potential duration (APD). Reference quinolones, sparfloxacin (3-30 microM) and moxifloxacin (10-100 microM), had no effects on RMP and APA, but significantly prolonged APD at more than 3 and 10 microM, respectively, while ciprofloxacin (10-100 microM) had no effect on each parameter. In vivo electrophysiology study using anesthetized dogs: PZFX mesilate had no effects on electrocardiograph parameter (PR interval, QRS interval, QT interval and QTc) after intravenous administration of 3-30 mg/kg. These results suggest that PZFX mesilate has low potential for QT interval prolongation.
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Varela, Marta; Hancox, Jules C.; Aslanidi, Oleg V.
2016-01-01
Anti-arrhythmic drug therapy is a frontline treatment for atrial fibrillation (AF), but its success rates are highly variable. This is due to incomplete understanding of the mechanisms of action of specific drugs on the atrial substrate at different stages of AF progression. We aimed to elucidate the role of cellular, tissue and organ level atrial heterogeneities in the generation of a re-entrant substrate during AF progression, and their modulation by the acute action of selected anti-arrhythmic drugs. To explore the complex cell-to-organ mechanisms, a detailed biophysical models of the entire 3D canine atria was developed. The model incorporated atrial geometry and fibre orientation from high-resolution micro-computed tomography, region-specific atrial cell electrophysiology and the effects of progressive AF-induced remodelling. The actions of multi-channel class III anti-arrhythmic agents vernakalant and amiodarone were introduced in the model by inhibiting appropriate ionic channel currents according to experimentally reported concentration-response relationships. AF was initiated by applied ectopic pacing in the pulmonary veins, which led to the generation of localized sustained re-entrant waves (rotors), followed by progressive wave breakdown and rotor multiplication in both atria. The simulated AF scenarios were in agreement with observations in canine models and patients. The 3D atrial simulations revealed that a re-entrant substrate was typically provided by tissue regions of high heterogeneity of action potential duration (APD). Amiodarone increased atrial APD and reduced APD heterogeneity and was more effective in terminating AF than vernakalant, which increased both APD and APD dispersion. In summary, the initiation and sustenance of rotors in AF is linked to atrial APD heterogeneity and APD reduction due to progressive remodelling. Our results suggest that anti-arrhythmic strategies that increase atrial APD without increasing its dispersion are effective in terminating AF. PMID:27984585
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Zhao, Meimi; Zhao, Jinsheng; He, Guilin; Sun, Xuefei; Huang, Xueshi; Hao, Liying
2013-01-01
Astragaloside IV (AS-IV) is one of the main active constituents of Astragalus membranaceus, which has various actions on the cardiovascular system. However, its electrophysiological mechanisms are not clear. In the present study, we investigated the effects of AS-IV on action potentials and membrane currents using the whole-cell patch clamp technique in isolated guinea-pig ventricular myocytes. AS-IV prolonged the action potential duration (APD) at all three tested concentrations. The peak effect was achieved with 1×10(-6) M, at which concentration AS-IV significantly prolonged the APD at 95% repolarization from 313.1±38.9 to 785.3±83.7 ms. AS-IV at 1×10(-6) M also enhanced the inward rectifier K(+) currents (I(K1)) and inhibited the delayed rectifier K(+) currents (I(K)). AS-IV (1×10(-6) M) strongly depressed the peak of voltage-dependent Ca(2+) channel current (I(CaL)) from -607.3±37.5 to -321.1±38.3 pA. However, AS-IV was not found to affect the Na(+) currents. Taken together, AS-IV prolonged APD of guinea-pig ventricular myocytes, which might be explained by its inhibition of I(K). AS-IV also influences Ca(2+) signaling through suppressing ICaL.
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Zhu, Yujie; Ai, Xun; Oster, Robert A; Bers, Donald M; Pogwizd, Steven M
2013-06-01
Slow delayed rectifier potassium current (IKs) is important in action potential (AP) repolarization and repolarization reserve. We tested the hypothesis that there are sex-specific differences in IKs, AP, and their regulation by β-adrenergic receptors (β-AR's) using whole-cell patch-clamp. AP duration (APD90) was significantly longer in control female (F) than in control male (M) myocytes. Isoproterenol (ISO, 500 nM) shortened APD90 comparably in M and F, and was largely reversed by β1-AR blocker CGP 20712A (CGP, 300 nM). Inhibition of IKs with chromanol 293B (10 μM) resulted in less APD prolongation in F at baseline (3.0 vs 8.9 %, p < 0.05 vs M) and even in the presence of ISO (5.4 vs 20.9 %, p < 0.05). This suggests that much of the ISO-induced APD abbreviation in F is independent of IKs. In F, baseline IKs was 42 % less and was more weakly activated by ISO (19 vs 68 % in M, p < 0.01). ISO enhancement of IKs was comparably attenuated by CGP in M and F. After ovariectomy, IKs in F had greater enhancement by ISO (72 %), now comparable to control M. After orchiectomy, IKs in M was only slightly enhanced by ISO (23 %), comparable to control F. Pretreatment with thapsigargin (to block SR Ca release) had bigger impact on ISO-induced APD shortening in F than that in M (p < 0.01). In conclusion, we found that there are sex differences in IKs, AP, and their regulation by β-AR's that are modulated by sex hormones, suggesting the potential for sex-specific antiarrhythmic therapy.
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Curvature effects on activation speed and repolarization in an ionic model of cardiac myocytes
NASA Astrophysics Data System (ADS)
Comtois, P.; Vinet, A.
1999-10-01
Reentry is a major mechanism underlying the initiation and perpetuation of many cardiac arrhythmias 12345. Stimulated ventricular myocytes give action potential characterized by a fast upstroke, a long-lasting plateau, and a late repolarization phase. The plateau phase determines the action potential duration (APD) during which the system remains refractory, a property essential to the synchronization of the heart cycle. The APD varies much with prematurity and this change has been shown to be the main determinant of the dynamics in models of paced cells and cable, and during reentry in the one-dimensional loop. Curvature has also been shown to be an important factor for propagation in experimental and theoretical cardiac extended tissue. The objective of this paper is to combine both curvature and prematurity effects in a kinematical model of propagation in cardiac tissue. First, an approximation of the ionic model is used to obtain the effects of curvature and prematurity on the speed of propagation, the APD, and the absolute refractory period. Two versions of the ionic model are studied that differ in their rate of excitability recovery. The functions are used in a kinematical model describing the propagation of period-1 solutions around an annulus.
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Taccardi, Bruno; Punske, Bonnie B; Sachse, Frank; Tricoche, Xavier; Colli-Franzone, Piero; Pavarino, Luca F; Zabawa, Christine
2005-10-01
There are no published data showing the three-dimensional sequence of repolarization and the associated potential fields in the ventricles. Knowledge of the sequence of repolarization has medical relevance because high spatial dispersion of recovery times and action potential durations favors cardiac arrhythmias. In this study we describe measured and simulated 3-D excitation and recovery sequences and activation-recovery intervals (ARIs) (measured) or action potential durations (APDs) (simulated) in the ventricular walls. We recorded from 600 to 1400 unipolar electrograms from canine ventricular walls during atrial and ventricular pacing at 350-450 ms cycle length. Measured excitation and recovery times and ARIs were displayed as 2-D maps in transmural planes or 3-D maps in the volume explored, using specially developed software. Excitation and recovery sequences and APD distributions were also simulated in parallelepipedal slabs using anisotropic monodomain or bidomain models based on the Lou-Rudy version 1 model with homogeneous membrane properties. Simulations showed that in the presence of homogeneous membrane properties, the sequence of repolarization was similar but not identical to the excitation sequence. In a transmural plane perpendicular to epicardial fiber direction, both activation and recovery pathways starting from an epicardial pacing site returned toward the epicardium at a few cm distance from the pacing site. However, APDs were not constant, but had a dispersion of approximately 14 ms in the simulated domain. The maximum APD value was near the pacing site and two minima appeared along a line perpendicular to fiber directions, passing through the pacing site. Electrical measurements in dog ventricles showed that, for short cycle lengths, both excitation and recovery pathways, starting from an epicardial pacing site, returned toward the epicardium. For slower pacing rates, pathways of recovery departed from the pathway of excitation. Highest ARI values were observed near the pacing site in part of the experiments. In addition, maps of activation-recovery intervals showed mid-myocardial clusters with activation-recovery intervals that were slightly longer than ARIs closer to the epi- or endocardium, suggesting the presence of M cells in those areas. Transmural dispersion of measured ARIs was on the order of 20-25 ms. Potential distributions during recovery were less affected by myocardial anisotropy than were excitation potentials.
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The changes of potassium currents in rabbit ventricle with healed myocardial infarction.
Liu, Nian; Niu, Huiyan; Li, Yang; Zhang, Cuntai; Zhou, Qiang; Ruan, Yanfei; Pu, Jun; Lu, Zaiying
2004-01-01
To elucidate the mechanism of arrhythmia in healed myocardial infarction (HMI), the changes of action potential duration (APD), transient outward potassium current (Ito), delayed rectifier potassium current (IK) and inward rectifier potassium current (IK1) of left ventricular myocytes in non-infarcted zone of HMI were investigated. Rabbits were randomly assigned into two groups: HMI group, in which animals were subjected to thoracotomy and ligation of the circumflex coronary and sham-operated group, in which rabbits underwent thoracotomy but no conorary ligation. 3 months after the operation, the whole myocyte patch clamp technique was used to record APD, Ito, IK, and IK1 of ventricular myocytes in non-infarcted zone. Our results showed that the membrane capacitance was larger in HMI group than in sham-operated group. Action potential duration was significantly lengthened in HMI group and early afterdepolarization (EAD) appeared in HMI group. The densities of Ito, I(K, tail), and IK1 were reduced significantly in HMI group, from 6.72 +/- 0.42 pA/pF, 1.54 +/- 0.13 pA/pF and 25.6 +/- 2.6 pA/pF in sham-operated group to 4.03 +/- 0.33 pA/pF, 1.14 +/- 0.11 pA/pF and 17.6 +/- 2.3 pA/pF, respectively. It is concluded that the reduced densities of Ito, I(K, tail) and IK1 in ventricular myocytes of non-infarcted zone in HMI were responsible for the prolongation of APD and the presentation of EAD which played important roles in the development of malignant arrhythmia in HMI.
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Cardiovascular Safety Pharmacology of Sibutramine.
Yun, Jaesuk; Chung, Eunyong; Choi, Ki Hwan; Cho, Dae Hyun; Song, Yun Jeong; Han, Kyoung Moon; Cha, Hey Jin; Shin, Ji Soon; Seong, Won-Keun; Kim, Young-Hoon; Kim, Hyung Soo
2015-07-01
Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an IC50 of 3.92 μM in patch clamp assay and increased the heart rate and blood pressure (76 Δbpm in heart rate and 51 ΔmmHg in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at 10 μM and 30 μM, resulted in 15% and 29% decreases in APD50, and 9% and 17% decreases in APD90, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation.
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NASA Astrophysics Data System (ADS)
Gulothungan, G.; Malathi, R.
2018-04-01
Disturbed sodium (Na+) and calcium (Ca2+) handling is known to be a major predisposing factor for life-threatening cardiac arrhythmias. Cardiac contractility in ventricular tissue is prominent by Ca2+ channels like voltage dependent Ca2+ channels, sodium-calcium exchanger (Na+-Ca2+x) and sacroplasmicrecticulum (SR) Ca2+ pump and leakage channels. Experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. Our aim of this article is to study the impact on action potential (AP) generation and propagation in single ventricular myocyte and ventricular tissue under different dysfunction Ca2+ channels condition. In enhanced activity of Na+-Ca2+x, single myocyte produces AP duration (APD90) and APD50 is significantly smaller (266 ms and 235 ms). Its Na+-Ca2+x current at depolarization is increases 60% from its normal level and repolarization current goes more negative (nonfailing= -0.28 pA/pF and failing= -0.47 pA/pF). Similarly, same enhanced activity of Na+-Ca2+x in 10 mm region of ventricular sheet, raises the plateau potential abruptly, which ultimately affects the diastolic repolarization. Compare with normal ventricular sheet region of 10 mm, 10% of ventricular sheet resting state is reduces and ventricular sheet at time 250 ms is goes to resting state very early. In hypertrophy condition, single myocyte produces APD90 and APD50 is worthy of attention smaller (232 mS and 198 ms). Its sodium-potassium (Na+-K+) pump current is 75% reduces from its control conditions (0.13 pA/pF). Hypertrophy condition, 50% of ventricular sheet is reduces to minimum plateau potential state, that starts the repolarization process very early and reduces the APD. In a single failing SR Ca2+ channels myocyte, recovery of Ca2+ concentration level in SR reduces upto 15% from its control myocytes. At time 290 ms, 70% of ventricular sheet is in dysfunction resting potential state in the range -83 mV and ventricular sheet at time 295 ms is goes to 65% dysfunction resting state. Therefore we concluded that shorter APD, instability resting potential and affected calcium induced calcium release (CICR) due to dysfunction Ca2+ channels is potentially have a substantial effect on cardiac contractility and relaxation. Computational study on ventricular tissue AP and its underlying ionic channel currents could help to elucidate possible arrhythmogenic mechanism on a cellular level.
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Bifurcation theory and cardiac arrhythmias
Karagueuzian, Hrayr S; Stepanyan, Hayk; Mandel, William J
2013-01-01
In this paper we review two types of dynamic behaviors defined by the bifurcation theory that are found to be particularly useful in describing two forms of cardiac electrical instabilities that are of considerable importance in cardiac arrhythmogenesis. The first is action potential duration (APD) alternans with an underlying dynamics consistent with the period doubling bifurcation theory. This form of electrical instability could lead to spatially discordant APD alternans leading to wavebreak and reentrant form of tachyarrhythmias. Factors that modulate the APD alternans are discussed. The second form of bifurcation of importance to cardiac arrhythmogenesis is the Hopf-homoclinic bifurcation that adequately describes the dynamics of the onset of early afterdepolarization (EAD)-mediated triggered activity (Hopf) that may cause ventricular tachycardia and ventricular fibrillation (VT/VF respectively). The self-termination of the triggered activity is compatible with the homoclinic bifurcation. Ionic and intracellular calcium dynamics underlying these dynamics are discussed using available experimental and simulation data. The dynamic analysis provides novel insights into the mechanisms of VT/VF, a major cause of sudden cardiac death in the US. PMID:23459417
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Yin, Dechun; Chen, Mu; Yang, Na; Wu, Adonis Z; Xu, Dongzhu; Tsai, Wei-Chung; Yuan, Yuan; Tian, Zhipeng; Chan, Yi-Hsin; Shen, Changyu; Chen, Zhenhui; Lin, Shien-Fong; Weiss, James N; Chen, Peng-Sheng; Everett, Thomas H
2018-05-01
Apamin-sensitive small conductance calcium-activated K current (I KAS ) is up-regulated during ventricular pacing and masks short-term cardiac memory (CM). The purpose of this study was to determine the role of I KAS in long-term CM. CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T wave off pacing. Epicardial optical mapping was performed in both paced and normal ventricles. Action potential duration (APD 80 ) was determined during right atrial pacing. Ventricular stability was tested before and after I KAS blockade. Four paced hearts and 4 normal hearts were used for western blotting and histology. There were no significant differences in either echocardiographic parameters or fibrosis levels between groups. Apamin induced more APD 80 prolongation in CM than in normal ventricles (mean [95% confidence interval]: 9.6% [8.8%-10.5%] vs 3.1% [1.9%-4.3%]; P <.001). Apamin significantly lengthened APD 80 in the CM model at late activation sites, indicating significant I KAS up-regulation at those sites. The CM model also had altered Ca 2+ handling, with the 50% Ca 2+ transient duration and amplitude increased at distal sites compared to a proximal site (near the pacing site). After apamin, the CM model had increased ventricular fibrillation (VF) inducibility (paced vs control: 33/40 (82.5%) vs 7/20 (35%); P <.001) and longer VF durations (124 vs 26 seconds; P <.001). Chronic ventricular pacing increases Ca 2+ transients at late activation sites, which activates I KAS to maintain repolarization reserve. I KAS blockade increases VF vulnerability in chronically paced rabbit ventricles. Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
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Computational modeling for cardiac safety pharmacology analysis: Contribution of fibroblasts.
Gao, Xin; Engel, Tyler; Carlson, Brian E; Wakatsuki, Tetsuro
2017-09-01
Drug-induced proarrhythmic potential is an important regulatory criterion in safety pharmacology. The application of in silico approaches to predict proarrhythmic potential of new compounds is under consideration as part of future guidelines. Current approaches simulate the electrophysiology of a single human adult ventricular cardiomyocyte. However, drug-induced proarrhythmic potential can be different when cardiomyocytes are surrounded by non-muscle cells. Incorporating fibroblasts in models of myocardium is important particularly for predicting a drugs cardiac liability in the aging population - a growing population who take more medications and exhibit increased cardiac fibrosis. In this study, we used computational models to investigate the effects of fibroblast coupling on the electrophysiology and response to drugs of cardiomyocytes. A computational model of cardiomyocyte electrophysiology and ion handling (O'Hara, Virag, Varro, & Rudy, 2011) is coupled to a passive model of fibroblast electrophysiology to test the effects of three compounds that block cardiomyocyte ion channels. Results are compared to model results without fibroblast coupling to see how fibroblasts affect cardiomyocyte action potential duration at 90% repolarization (APD 90 ) and propensity for early after depolarization (EAD). Simulation results show changes in cardiomyocyte APD 90 with increasing concentration of three drugs that affect cardiac function (dofetilide, vardenafil and nebivolol) when no fibroblasts are coupled to the cardiomyocyte. Coupling fibroblasts to cardiomyocytes markedly shortens APD 90 . Moreover, increasing the number of fibroblasts can augment the shortening effect. Coupling cardiomyocytes and fibroblasts are predicted to decrease proarrhythmic susceptibility under dofetilide, vardenafil and nebivolol block. However, this result is sensitive to parameters which define the electrophysiological function of the fibroblast. Fibroblast membrane capacitance and conductance (C FB and G FB ) have less of an effect on APD 90 than the fibroblast resting membrane potential (E FB ). This study suggests that in both theoretical models and experimental tissue constructs that represent cardiac tissue, both cardiomyocytes and non-muscle cells should be considered when testing cardiac pharmacological agents. Copyright © 2017 Elsevier Inc. All rights reserved.
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Schmidt, Constanze; Wiedmann, Felix; Voigt, Niels; Zhou, Xiao-Bo; Heijman, Jordi; Lang, Siegfried; Albert, Virginia; Kallenberger, Stefan; Ruhparwar, Arjang; Szabó, Gábor; Kallenbach, Klaus; Karck, Matthias; Borggrefe, Martin; Biliczki, Peter; Ehrlich, Joachim R; Baczkó, István; Lugenbiel, Patrick; Schweizer, Patrick A; Donner, Birgit C; Katus, Hugo A; Dobrev, Dobromir; Thomas, Dierk
2015-07-14
Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K(2P)3.1 (TASK-1 [tandem of P domains in a weak inward-rectifying K+ channel-related acid-sensitive K+ channel-1]) 2-pore-domain K+ (K(2P)) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic patients with AF is unknown. Right and left atrial tissue was obtained from patients with paroxysmal or chronic AF and from control subjects in sinus rhythm. Ion channel expression was analyzed by quantitative real-time polymerase chain reaction and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K(2P)3.1 subunits exhibited predominantly atrial expression, and atrial K(2P)3.1 transcript levels were highest among functional K(2P) channels. K(2P)3.1 mRNA and protein levels were increased in chronic AF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD90) compared with patients in sinus rhythm. In contrast, K(2P)3.1 expression was not significantly affected in subjects with paroxysmal AF. Pharmacological K(2P)3.1 inhibition prolonged APD90 in atrial myocytes from patients with chronic AF to values observed among control subjects in sinus rhythm. Enhancement of atrium-selective K(2P)3.1 currents contributes to APD shortening in patients with chronic AF, and K(2P)3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K(2P)3.1 as a novel drug target for mechanism-based AF therapy. © 2015 American Heart Association, Inc.
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Tran, Diana X; Yang, Ming-Jim; Weiss, James N; Garfinkel, Alan; Qu, Zhilin
2007-12-01
Ventricular fibrillation is a lethal arrhythmia characterized by multiple wavelets usually starting from a single or figure-of-eight re-entrant circuit. Understanding the factors regulating vulnerability to the re-entry is essential for developing effective therapeutic strategies to prevent ventricular fibrillation. In this study, we investigated how pre-existing tissue heterogeneities and electrical restitution properties affect the initiation of re-entry by premature extrastimuli in two-dimensional cardiac tissue models. We studied two pacing protocols for inducing re-entry following the "sinus" rhythm (S1) beat: (1) a single premature (S2) extrastimulus in heterogeneous tissue; (2) two premature extrastimuli (S2 and S3) in homogeneous tissue. In the first case, the vulnerable window of re-entry is determined by the spatial dimension and extent of the heterogeneity, and is also affected by electrical restitution properties and the location of the premature stimulus. The vulnerable window first increases as the action potential duration (APD) difference between the inside and outside of the heterogeneous region increases, but then decreases as this difference increases further. Steeper APD restitution reduces the vulnerable window of re-entry. In the second case, electrical restitution plays an essential role. When APD restitution is flat, no re-entry can be induced. When APD restitution is steep, re-entry can be induced by an S3 over a range of S1S2 intervals, which is also affected by conduction velocity restitution. When APD restitution is even steeper, the vulnerable window is reduced due to collision of the spiral tips.
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Distinguishing mechanisms for alternans in cardiac cells using constant-diastolic-interval pacing
NASA Astrophysics Data System (ADS)
Cherry, Elizabeth M.
2017-09-01
Alternans, a proarrhythmic dynamical state in which cardiac action potentials alternate between long and short durations despite a constant pacing period, traditionally has been explained at the cellular level using nonlinear dynamics principles under the assumption that the action potential duration (APD) is determined solely by the time elapsed since the end of the previous action potential, called the diastolic interval (DI). In this scenario, APDs at a steady state should be the same provided that the preceding DIs are the same. Nevertheless, experiments attempting to eliminate alternans by dynamically adjusting the timing of pacing stimuli to keep the DI constant showed that alternans persisted, contradicting the traditional theory. It is now widely known that alternans also can arise from a different mechanism associated with intracellular calcium cycling. Our goal is to determine whether intracellular calcium dynamics can explain the experimental findings regarding the persistence of alternans despite a constant DI. For this, we use mathematical models capable of producing alternans through both voltage- and calcium-mediated mechanisms. We show that for voltage-driven alternans, action potentials elicited from a constant-DI protocol are always the same. However, in the case of calcium-driven alternans, the constant-DI protocol can result in alternans. Reducing the strength of the calcium instability progressively reduces and finally eliminates constant-DI alternans. Our findings suggest that screening for the presence of alternans using a constant-DI protocol has the potential for differentiating between voltage-driven and calcium-driven alternans.
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Floré, Vincent; Claus, Piet; Symons, Rolf; Smith, Godfrey L; Sipido, Karin R; Willems, Rik
2013-08-01
There is convincing experimental evidence that cellular action potential duration (APD) alternans is arrhythmogenic but its relationship with body surface microvolt T-wave alternans (MTWA) remains unclear. We investigated the relationship between MTWA and APD alternans induced by alternating cycle length (CL) pacing in a pig model. In 10 pigs, catheters in the right atrium (RA) and right (RV) and left ventricle (LV) allowed pacing and recording of monophasic action potentials (MAP). During RA pacing at stable 500-ms CL, LV was paced at alternating CL (505 ms and 495 ms). Changing the alternating LV (A-LV) pacing delay changes the size of the region with alternating ventricular activation. Spectral analysis of intracardiac MAP was correlated with body surface MTWA. In a similar setup (during alternating pacing in RV and LV), we investigated concordant versus discordant APD alternans. Pacing the LV with subtle alternating cycle lengths at short A-LV delay leads to broad QRS (97 ± 10 ms), body surface MTWA (mean Valt 4.2 ± 1.8 µV), and positive RR-interval alternans. At longer A-LV delay, not resulting in QRS widening (68 ± 5 ms), body surface RR alternans was absent but MTWA remained detectable and was even more pronounced (8.7 ± 5.1 µV, P < 0.01). During both concordant and discordant pacing MTWA was present. The precordial leads were better for detecting discordant APD alternans (8.0 ± 2.9 µV and 12.8 ± 4.52 µV, P = 0.02). MTWA is a potent technique to detect subtle and isolated intracardiac APD alternans that is artificially induced by alternating pacing. In the same model, discordant activation alternans can only be discriminated from concordant when using a quantifying approach of MTWA analysis. ©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.
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Yang, Baode; Li, Chenxing; Sun, Junyi; Wang, Xinghui; Liu, Xinling; Yang, Chun; Chen, Lina; Zhou, Jun; Hu, Hao
2017-05-01
Excessive consumption of alcohol is a well-established risk factor of atrial fibrillation (AF). However, the effects of moderate alcohol drinking remain to be elucidated. This study was designed to determine the effects of moderate ethanol ingestion on atrial fibrillation and the electrophysiological mechanisms. In acetylcholine-induced canine and mouse AF models, the moderate ethanol prevented the generation and persistence of AF through prolonging the latent period of AF and shortening the duration of AF. The action potential duration (APD) was remarkably prolonged under the concentration range of 12.5-50.0mM ethanol in guinea pig atrial myocytes. Ultra-rapid delayed rectified potassium currents (I Kv1.5 ) were markedly inhibited by 12.5-50.0mM ethanol in a concentration-dependent manner. Ethanol with 50.0mM could inhibit rapid delayed rectifier potassium currents (I hERG ). Ethanol under 6.25-50.0mM did not affect on inward rectifier potassium currents (I Kir2.1 ). Collectively, the present study provided an evidence that moderate ethanol intake can prolong the APD of atrial myocytes by inhibition of I Kv1.5 and I hERG , which contributed to preventing the development and duration of AF. Copyright © 2017 Elsevier Inc. All rights reserved.
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Maleckar, Mary M; Lines, Glenn T; Koivumäki, Jussi T; Cordeiro, Jonathan M; Calloe, Kirstine
2014-11-01
The study investigates how increased Ito, as mediated by the activator NS5806, affects excitation-contraction coupling in chronic heart failure (HF). We hypothesized that restoring spike-and-dome morphology of the action potential (AP) to a healthy phenotype would be insufficient to restore the intracellular Ca(2) (+) transient (CaT), due to HF-induced remodelling of Ca(2+) handling. An existing mathematical model of the canine ventricular myocyte was modified to incorporate recent experimental data from healthy and failing myocytes, resulting in models of both healthy and HF epicardial, midmyocardial, and endocardial cell variants. Affects of NS5806 were also included in HF models through its direct interaction with Kv4.3 and Kv1.4. Single-cell simulations performed in all models (control, HF, and HF + drug) and variants (epi, mid, and endo) assessed AP morphology and underlying ionic processes with a focus on calcium transients (CaT), how these were altered in HF across the ventricular wall, and the subsequent effects of varying compound concentration in HF. Heart failure model variants recapitulated a characteristic increase in AP duration (APD) in the disease. The qualitative effects of application of half-maximal effective concentration (EC50) of NS5806 on APs and CaT are heterogeneous and non-linear. Deepening in the AP notch with drug is a direct effect of the activation of Ito; both Ito and consequent alteration of IK1 kinetics cause decrease in AP plateau potential. Decreased APD50 and APD90 are both due to altered IK1. Analysis revealed that drug effects depend on transmurality. Ca(2+) transient morphology changes-increased amplitude and shorter time to peak-are due to direct increase in ICa,L and indirect larger SR Ca(2+) release subsequent to Ito activation. Downstream effects of a compound acting exclusively on sarcolemmal ion channels are difficult to predict. Remediation of APD to pre-failing state does not ameliorate dysfunction in CaT; however, restoration of notch depth appears to impart modest benefit and a likelihood of therapeutic value in modulating early repolarization. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
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Sympathetic Nervous Regulation of Calcium and Action Potential Alternans in the Intact Heart.
Winter, James; Bishop, Martin J; Wilder, Catherine D E; O'Shea, Christopher; Pavlovic, Davor; Shattock, Michael J
2018-01-01
Rationale: Arrhythmogenic cardiac alternans are thought to be an important determinant for the initiation of ventricular fibrillation. There is limited information on the effects of sympathetic nerve stimulation (SNS) on alternans in the intact heart and the conclusions of existing studies, focused on investigating electrical alternans, are conflicted. Meanwhile, several lines of evidence implicate instabilities in Ca handling, not electrical restitution, as the primary mechanism underpinning alternans. Despite this, there have been no studies on Ca alternans and SNS in the intact heart. The present study sought to address this, by application of voltage and Ca optical mapping for the simultaneous study of APD and Ca alternans in the intact guinea pig heart during direct SNS. Objective : To determine the effects of SNS on APD and Ca alternans in the intact guinea pig heart and to examine the mechanism(s) by which the effects of SNS are mediated. Methods and Results : Studies utilized simultaneous voltage and Ca optical mapping in isolated guinea pig hearts with intact innervation. Alternans were induced using a rapid dynamic pacing protocol. SNS was associated with rate-independent shortening of action potential duration (APD) and the suppression of APD and Ca alternans, as indicated by a shift in the alternans threshold to faster pacing rates. Qualitatively similar results were observed with exogenous noradrenaline perfusion. In contrast with previous reports, both SNS and noradrenaline acted to flatten the slope of the electrical restitution curve. Pharmacological block of the slow delayed rectifying potassium current (I Ks ), sufficient to abolish I Ks -mediated APD-adaptation, partially reversed the effects of SNS on pacing-induced alternans. Treatment with cyclopiazonic acid, an inhibitor of the sarco(endo)plasmic reticulum ATPase, had opposite effects to that of SNS, acting to increase susceptibility to alternans, and suggesting that accelerated Ca reuptake into the sarcoplasmic reticulum is a major mechanism by which SNS suppresses alternans in the guinea pig heart. Conclusions : SNS suppresses calcium and action potential alternans in the intact guinea pig heart by an action mediated through accelerated Ca handling and via increased I Ks .
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Two-Term Asymptotic Approximation of a Cardiac Restitution Curve*
Cain, John W.; Schaeffer, David G.
2007-01-01
If spatial extent is neglected, ionic models of cardiac cells consist of systems of ordinary differential equations (ODEs) which have the property of excitability, i.e., a brief stimulus produces a prolonged evolution (called an action potential in the cardiac context) before the eventual return to equilibrium. Under repeated stimulation, or pacing, cardiac tissue exhibits electrical restitution: the steady-state action potential duration (APD) at a given pacing period B shortens as B is decreased. Independent of ionic models, restitution is often modeled phenomenologically by a one-dimensional mapping of the form APDnext = f(B – APDprevious). Under some circumstances, a restitution function f can be derived as an asymptotic approximation to the behavior of an ionic model. In this paper, extending previous work, we derive the next term in such an asymptotic approximation for a particular ionic model consisting of two ODEs. The two-term approximation exhibits excellent quantitative agreement with the actual restitution curve, whereas the leading-order approximation significantly underestimates actual APD values. PMID:18080006
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Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs.
Xie, Chaoqin; Biary, Nora; Tocchetti, Carlo G; Aon, Miguel A; Paolocci, Nazareno; Kauffman, Justin; Akar, Fadi G
2013-04-01
Chronic hyperglycemia in type-1 diabetes mellitus is associated with oxidative stress (OS) and sudden death. Mechanistic links remain unclear. We investigated changes in electrophysiological (EP) properties in a model of chronic hyperglycemia before and after challenge with OS by GSH oxidation and tested reversibility of EP remodeling by insulin. Guinea pigs survived for 1 mo following streptozotocin (STZ) or saline (sham) injection. A treatment group received daily insulin for 2 wk to reverse STZ-induced hyperglycemia (STZ + Ins). EP properties were measured using high-resolution optical action potential mapping before and after challenge of hearts with diamide. Despite elevation of glucose levels in STZ compared with sham-operated (P = 0.004) and STZ + Ins (P = 0.002) animals, average action potential duration (APD) and arrhythmia propensity were not altered at baseline. Diamide promoted early (<10 min) formation of arrhythmic triggers reflected by a higher arrhythmia scoring index in STZ (P = 0.045) and STZ + Ins (P = 0.033) hearts compared with sham-operated hearts. APD heterogeneity underwent a more pronounced increase in response to diamide in STZ and STZ + Ins hearts compared with sham-operated hearts. Within 30 min, diamide resulted in spontaneous incidence of ventricular tachycardia and ventricular fibrillation (VT/VF) in 3/6, 2/5, 1/5, and 0/4 STZ, STZ + Ins, sham-operated, and normal hearts, respectively. Hearts prone to VT/VF exhibited greater APD heterogeneity (P = 0.010) compared with their VT/VF-free counterparts. Finally, altered EP properties in STZ were not rescued by insulin. In conclusion, GSH oxidation enhances APD heterogeneity and increases arrhythmia scoring index in a guinea pig model of chronic hyperglycemia. Despite normalization of glycemic levels by insulin, these proarrhythmic properties are not reversed, suggesting the importance of targeting antioxidant defenses for arrhythmia suppression.
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Human ex-vivo action potential model for pro-arrhythmia risk assessment.
Page, Guy; Ratchada, Phachareeya; Miron, Yannick; Steiner, Guido; Ghetti, Andre; Miller, Paul E; Reynolds, Jack A; Wang, Ken; Greiter-Wilke, Andrea; Polonchuk, Liudmila; Traebert, Martin; Gintant, Gary A; Abi-Gerges, Najah
2016-01-01
While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach. Copyright © 2016 Elsevier Inc. All rights reserved.
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Schweigmann, Ulrich; Biliczki, Peter; Ramirez, Rafael J; Marschall, Christoph; Takac, Ina; Brandes, Ralf P; Kotzot, Dieter; Girmatsion, Zenawit; Hohnloser, Stefan H; Ehrlich, Joachim R
2014-01-01
Long QT syndrome (LQTS) leads to arrhythmic events and increased risk for sudden cardiac death (SCD). Homozygous KCNH2 mutations underlying LQTS-2 have previously been termed "human HERG knockout" and typically express severe phenotypes. We studied genotype-phenotype correlations of an LQTS type 2 mutation identified in the homozygous index patient from a consanguineous Turkish family after his brother died suddenly during febrile illness. Clinical work-up, DNA sequencing, mutagenesis, cell culture, patch-clamp, in silico mathematical modelling, protein biochemistry, confocal microscopy were performed. Genetic analysis revealed a homozygous C-terminal KCNH2 mutation (p.R835Q) in the index patient (QTc ∼506 ms with notched T waves). Parents were I° cousins - both heterozygous for the mutation and clinically unremarkable (QTc ∼447 ms, father and ∼396 ms, mother). Heterologous expression of KCNH2-R835Q showed mildly reduced current amplitudes. Biophysical properties of ionic currents were also only nominally changed with slight acceleration of deactivation and more negative V50 in R835Q-currents. Protein biochemistry and confocal microscopy revealed similar expression patterns and trafficking of WT and R835Q, even at elevated temperature. In silico analysis demonstrated mildly prolonged ventricular action potential duration (APD) compared to WT at a cycle length of 1000 ms. At a cycle length of 350 ms M-cell APD remained stable in WT, but displayed APD alternans in R835Q. Kv11.1 channels affected by the C-terminal R835Q mutation display mildly modified biophysical properties, but leads to M-cell APD alternans with elevated heart rate and could precipitate SCD under specific clinical circumstances associated with high heart rates.
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Human ex-vivo action potential model for pro-arrhythmia risk assessment
Page, Guy; Ratchada, Phachareeya; Miron, Yannick; Steiner, Guido; Ghetti, Andre; Miller, Paul E; Reynolds, Jack A; Wang, Ken; Greiter-Wilke, Andrea; Polonchuk, Liudmila; Traebert, Martin; Gintant, Gary A; Abi-Gerges, Najah
2016-01-01
While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach. PMID:27235787
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Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs
Xie, Chaoqin; Biary, Nora; Tocchetti, Carlo G.; Aon, Miguel A.; Paolocci, Nazareno; Kauffman, Justin
2013-01-01
Chronic hyperglycemia in type-1 diabetes mellitus is associated with oxidative stress (OS) and sudden death. Mechanistic links remain unclear. We investigated changes in electrophysiological (EP) properties in a model of chronic hyperglycemia before and after challenge with OS by GSH oxidation and tested reversibility of EP remodeling by insulin. Guinea pigs survived for 1 mo following streptozotocin (STZ) or saline (sham) injection. A treatment group received daily insulin for 2 wk to reverse STZ-induced hyperglycemia (STZ + Ins). EP properties were measured using high-resolution optical action potential mapping before and after challenge of hearts with diamide. Despite elevation of glucose levels in STZ compared with sham-operated (P = 0.004) and STZ + Ins (P = 0.002) animals, average action potential duration (APD) and arrhythmia propensity were not altered at baseline. Diamide promoted early (<10 min) formation of arrhythmic triggers reflected by a higher arrhythmia scoring index in STZ (P = 0.045) and STZ + Ins (P = 0.033) hearts compared with sham-operated hearts. APD heterogeneity underwent a more pronounced increase in response to diamide in STZ and STZ + Ins hearts compared with sham-operated hearts. Within 30 min, diamide resulted in spontaneous incidence of ventricular tachycardia and ventricular fibrillation (VT/VF) in 3/6, 2/5, 1/5, and 0/4 STZ, STZ + Ins, sham-operated, and normal hearts, respectively. Hearts prone to VT/VF exhibited greater APD heterogeneity (P = 0.010) compared with their VT/VF-free counterparts. Finally, altered EP properties in STZ were not rescued by insulin. In conclusion, GSH oxidation enhances APD heterogeneity and increases arrhythmia scoring index in a guinea pig model of chronic hyperglycemia. Despite normalization of glycemic levels by insulin, these proarrhythmic properties are not reversed, suggesting the importance of targeting antioxidant defenses for arrhythmia suppression. PMID:23376824
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Cheng, Hongwei; Cannell, Mark B; Hancox, Jules C
2017-03-01
Transient outward potassium current (I to ) in the heart underlies phase 1 repolarization of cardiac action potentials and thereby affects excitation-contraction coupling. Small molecule activators of I to may therefore offer novel treatments for cardiac dysfunction, including heart failure and atrial fibrillation. NS5806 has been identified as a prototypic activator of canine I to This study investigated, for the first time, actions of NS5806 on rabbit atrial and ventricular I to Whole cell patch-clamp recordings of I to and action potentials were made at physiological temperature from rabbit ventricular and atrial myocytes. 10 μ mol/L NS5806 increased ventricular I to with a leftward shift in I to activation and accelerated restitution. At higher concentrations, stimulation of I to was followed by inhibition. The EC 50 for stimulation was 1.6 μ mol/L and inhibition had an IC 50 of 40.7 μ mol/L. NS5806 only inhibited atrial I to (IC 50 of 18 μ mol/L) and produced a modest leftward shifts in I to activation and inactivation, without an effect on restitution. 10 μ mol/L NS5806 shortened ventricular action potential duration (APD) at APD 20 -APD 90 but prolonged atrial APD NS5806 also reduced atrial AP upstroke and amplitude, consistent with an additional atrio-selective effect on Na + channels. In contrast to NS5806, flecainide, which discriminates between Kv1.4 and 4.x channels, produced similar levels of inhibition of ventricular and atrial I to NS5806 discriminates between rabbit ventricular and atrial I to, with mixed activator and inhibitor actions on the former and inhibitor actions against the later. NS5806 may be of significant value for pharmacological interrogation of regional differences in native cardiac I to . © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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CT-1-CP-induced ventricular electrical remodeling in mice.
Chen, Shu-fen; Wei, Tao-zhi; Rao, Li-ya; Xu, Ming-guang; Dong, Zhan-ling
2015-02-01
The chronic effects of carboxyl-terminal polypeptide of Cardiotrophin-1 (CT-1-CP) on ventricular electrical remodeling were investigated. CT-1-CP, which contains 16 amino acids in sequence of the C-terminal of Cardiotrophin-1, was selected and synthesized, and then administered to Kunming mice (aged 5 weeks) by intraperitoneal injection (500 ng·g⁻¹·day⁻¹) (4 groups, n=10 and female: male=1:1 in each group) for 1, 2, 3 and 4 weeks, respectively. The control group (n=10, female: male=1:1) was injected by physiological saline for 4 weeks. The epicardial monophasic action potential (MAP) was recorded by using a contact-type MAP electrode placed vertically on the left ventricular (LV) epicardium surface, and the electrocardiogram (ECG) signal in lead II was monitored synchronously. ECG intervals (RR, PR, QRS and QT) and the amplitude of MAP (Am), the maximum upstroke velocity (Vmax), as well as action potential durations (APDs) at different repolarization levels (APD30, APD50, APD70, and APD90) of MAP were determined and analyzed in detail. There were no significant differences in RR and P intervals between CT-1-CP-treated groups and control group, but the PR segment and the QRS complex were greater in the former than in the latter (F=2.681 and 5.462 respectively, P<0.05). Though QT interval and the corrected QT interval (QTc) were shorter in CT-1-CP-treated groups than in control group, the QT dispersion (QTd) of them was greater in the latter than in the former (F=3.090, P<0.05) and increased with the time. The ECG monitoring synchronously with the MAP showed that the compression of MAP electrode on the left ventricular epicardium induced performance similar to myocardium ischemia. As compared with those before chest-opening, the PR segment and QT intervals remained basically unchanged in control group, but prolonged significantly in all CT-1-CP-treated groups and the prolongation of QT intervals increased gradually along with the time of exposure to CT-1-CP. The QRS complex had no significant change in control group, one-week and three-week CT-1-CP-treated groups, but prolonged significantly in two-week and four-week CT-1-CP-treated groups. Interestingly, the QTd after chest-opening was significantly greater than that before chest-opening in control group (t=5.242, P<0.01), but decreased along with the time in CT-1-CP-treated groups. The mean MAP amplitude, Vmax and APD were greater in CT-1-CP-treated groups than those in control group, and became more obvious along with the time. The APD in four CT-1-CP-treat groups was prolonged mainly in middle to final repolarization phase. The difference among these groups became significant in middle phase (APD50) (F=6.076, P<0.01) and increased furthermore in late and final phases (APD70: F=10.054; APD90: F=18.691, P<0.01) along with the time of injection of CT-1-CP. The chronic action of CT-1-CP might induce the adapting alteration in cardiac conductivity and ventricular repolarization. The amplitude and the Vmax of the anterior LV epicardial MAP increased obviously, and the APD prolonged mainly in late and final phase of repolarization.
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Tao, Wen; Shi, Jianjian; Dorn, Gerald W.; Wei, Lei; Rubart, Michael
2012-01-01
Pathological left ventricular hypertrophy (LVH) is consistently associated with prolongation of the ventricular action potentials. A number of previous studies, employing various experimental models of hypertrophy, have revealed marked differences in the effects of hypertrophy on action potential duration (APD) between myocytes from endocardial and epicardial layers of the LV free wall. It is not known, however, whether pathological LVH is also accompanied by redistribution of APD among myocytes from the same layer in the LV free wall. In the experiments here, LV epicardial action potential remodeling was examined in a mouse model of decompensated LVH, produced by cardiac-restricted transgenic Gαq overexpression. Confocal linescanning-based optical recordings of propagated action potentials from individual in situ cardiomyocytes across the outer layer of the anterior LV epicardium demonstrated spatially non-uniform action potential prolongation in transgenic hearts, giving rise to alterations in spatial dispersion of epicardial repolarization. Local density and distribution of anti-Cx43 mmune reactivity in Gαq hearts were unchanged compared to wild-type hearts, suggesting preservation of intercellular coupling. Confocal microscopy also revealed heterogeneous disorganization of T-tubules in epicardial cardiomyocytes in situ. These data provide evidence of the existence of significant electrical and structural heterogeneity within the LV epicardial layer of hearts with transgenic Gαq overexpression-induced hypertrophy, and further support the notion that a small portion of electrically well connected LV tissue can maintain dispersion of action potential duration through heterogeneity in the activities of sarcolemmal ionic currents that control repolarization. It remains to be examined whether other experimental models of pathological LVH, including pressure overload LVH, similarly exhibit alterations in T-tubule organization and/or dispersion of repolarization within distinct layers of LV myocardium. PMID:22728217
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de Lorenzi, F G; Bridal, T R; Spinelli, W
1994-01-01
1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique. 2. Ondansetron and granisetron blocked IK with a KD of 1.7 +/- 1.0 and 4.3 +/- 1.7 microM, respectively. At a higher concentration (30 microM), both drugs blocked the inward rectifier (IKl). 3. The block of IK was dependent on channel activation. Both drugs slowed the decay of IK tail currents and produced a crossover with the pre-drug current trace. These results are consistent with block and unblock from the open state of the channel. 4. Granisetron showed an intrinsic voltage-dependence as the block increased with depolarization. The equivalent voltage-dependency of block (delta) was 0.10 +/- 0.04, suggesting that granisetron blocks from the intracellular side at a binding site located 10% across the transmembrane electrical field. 5. Ondansetron (1 microM) and granisetron (3 microM) prolonged APD by about 30% at 0.5 Hz. The prolongation of APD by ondansetron was abolished at faster frequencies (3 Hz) showing reverse rate dependence. 6. In conclusion, the 5-HT3 antagonists, ondansetron and granisetron, are open state blockers of the ventricular delayed rectifier and show a clear class III action. PMID:7834204
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Brown, Ninita H.; Dobrovolny, Hana M.; Gauthier, Daniel J.; Wolf, Patrick D.
2007-01-01
Optical fiber-based mapping systems are used to record the cardiac action potential (AP) throughout the myocardium. The optical AP contains a contraction-induced motion artifact (MA), which makes it difficult to accurately measure the action potential duration (APD). MA is removed by preventing contraction with electrical-mechanical uncoupling drugs, such as 2,3-butanedione monoxime (BDM). We designed a novel fiber-based ratiometric optical channel using a blue light emitting diode, a diffraction grating, and a split photodetector that can accurately measure the cardiac AP without the need for BDM. The channel was designed based on simulations using the optical design software ZEMAX. The channel has an electrical bandwidth of 150 Hz and an root mean-square dark noise of 742 μV. The channel successfully recorded the cardiac AP from the wall of five rabbit heart preparations without the use of BDM. After 20-point median filtering, the mean signal/noise ratio was 25.3 V/V. The APD measured from the base of a rabbit heart was 134 ± 8.4 ms, compared to 137.6 ± 3.3 ms from simultaneous microelectrode recordings. This difference was not statistically significant (p-value = 0.3). The quantity of MA removed was also measured using the motion ratio. The reduction in MA was significant (p-value = 0.0001). This fiber-based system is the first of its kind to enable optical APD measurements in the beating heart wall without the use of BDM. PMID:17416627
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Evaluation of Optogenetic Electrophysiology Tools in Human Stem Cell-Derived Cardiomyocytes.
Björk, Susann; Ojala, Elina A; Nordström, Tommy; Ahola, Antti; Liljeström, Mikko; Hyttinen, Jari; Kankuri, Esko; Mervaala, Eero
2017-01-01
Current cardiac drug safety assessments focus on hERG channel block and QT prolongation for evaluating arrhythmic risks, whereas the optogenetic approach focuses on the action potential (AP) waveform generated by a monolayer of human cardiomyocytes beating synchronously, thus assessing the contribution of several ion channels on the overall drug effect. This novel tool provides arrhythmogenic sensitizing by light-induced pacing in combination with non-invasive, all-optical measurements of cardiomyocyte APs and will improve assessment of drug-induced electrophysiological aberrancies. With the help of patch clamp electrophysiology measurements, we aimed to investigate whether the optogenetic modifications alter human cardiomyocytes' electrophysiology and how well the optogenetic analyses perform against this gold standard. Patch clamp electrophysiology measurements of non-transduced stem cell-derived cardiomyocytes compared to cells expressing the commercially available optogenetic constructs Optopatch and CaViar revealed no significant changes in action potential duration (APD) parameters. Thus, inserting the optogenetic constructs into cardiomyocytes does not significantly affect the cardiomyocyte's electrophysiological properties. When comparing the two methods against each other (patch clamp vs. optogenetic imaging) we found no significant differences in APD parameters for the Optopatch transduced cells, whereas the CaViar transduced cells exhibited modest increases in APD-values measured with optogenetic imaging. Thus, to broaden the screen, we combined optogenetic measurements of membrane potential and calcium transients with contractile motion measured by video motion tracking. Furthermore, to assess how optogenetic measurements can predict changes in membrane potential, or early afterdepolarizations (EADs), cells were exposed to cumulating doses of E-4031, a hERG potassium channel blocker, and drug effects were measured at both spontaneous and paced beating rates (1, 2 Hz). Cumulating doses of E-4031 produced prolonged APDs, followed by EADs and drug-induced quiescence. These observations were corroborated by patch clamp and contractility measurements. Similar responses, although more modest were seen with the I Ks potassium channel blocker JNJ-303. In conclusion, optogenetic measurements of AP waveforms combined with optical pacing compare well with the patch clamp gold standard. Combined with video motion contractile measurements, optogenetic imaging provides an appealing alternative for electrophysiological screening of human cardiomyocyte responses in pharmacological efficacy and safety testings.
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Evaluation of Optogenetic Electrophysiology Tools in Human Stem Cell-Derived Cardiomyocytes
Björk, Susann; Ojala, Elina A.; Nordström, Tommy; Ahola, Antti; Liljeström, Mikko; Hyttinen, Jari; Kankuri, Esko; Mervaala, Eero
2017-01-01
Current cardiac drug safety assessments focus on hERG channel block and QT prolongation for evaluating arrhythmic risks, whereas the optogenetic approach focuses on the action potential (AP) waveform generated by a monolayer of human cardiomyocytes beating synchronously, thus assessing the contribution of several ion channels on the overall drug effect. This novel tool provides arrhythmogenic sensitizing by light-induced pacing in combination with non-invasive, all-optical measurements of cardiomyocyte APs and will improve assessment of drug-induced electrophysiological aberrancies. With the help of patch clamp electrophysiology measurements, we aimed to investigate whether the optogenetic modifications alter human cardiomyocytes' electrophysiology and how well the optogenetic analyses perform against this gold standard. Patch clamp electrophysiology measurements of non-transduced stem cell-derived cardiomyocytes compared to cells expressing the commercially available optogenetic constructs Optopatch and CaViar revealed no significant changes in action potential duration (APD) parameters. Thus, inserting the optogenetic constructs into cardiomyocytes does not significantly affect the cardiomyocyte's electrophysiological properties. When comparing the two methods against each other (patch clamp vs. optogenetic imaging) we found no significant differences in APD parameters for the Optopatch transduced cells, whereas the CaViar transduced cells exhibited modest increases in APD-values measured with optogenetic imaging. Thus, to broaden the screen, we combined optogenetic measurements of membrane potential and calcium transients with contractile motion measured by video motion tracking. Furthermore, to assess how optogenetic measurements can predict changes in membrane potential, or early afterdepolarizations (EADs), cells were exposed to cumulating doses of E-4031, a hERG potassium channel blocker, and drug effects were measured at both spontaneous and paced beating rates (1, 2 Hz). Cumulating doses of E-4031 produced prolonged APDs, followed by EADs and drug-induced quiescence. These observations were corroborated by patch clamp and contractility measurements. Similar responses, although more modest were seen with the IKs potassium channel blocker JNJ-303. In conclusion, optogenetic measurements of AP waveforms combined with optical pacing compare well with the patch clamp gold standard. Combined with video motion contractile measurements, optogenetic imaging provides an appealing alternative for electrophysiological screening of human cardiomyocyte responses in pharmacological efficacy and safety testings. PMID:29163220
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Antzelevitch, Charles
2007-01-01
This review examines the role of spatial electrical heterogeneity within ventricular myocardium on the function of the heart in health and disease. The cellular basis for transmural dispersion of repolarization (TDR) is reviewed and the hypothesis that amplification of spatial dispersion of repolarization underlies the development of life-threatening ventricular arrhythmias associated with inherited ion channelopathies is evaluated. The role of TDR in the long QT, short QT and Brugada syndromes as well as catecholaminergic polymorphic ventricular tachycardia (CPVT) are critically examined. In the long QT Syndrome, amplification of TDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the Brugada Syndrome, it is thought to be due to selective abbreviation of the APD of right ventricular (RV) epicardium. Preferential abbreviation of APD of either endocardium or epicardium appears to be responsible for amplification of TDR in the short QT syndrome. In catecholaminergic polymorphic VT, reversal of the direction of activation of the ventricular wall is responsible for the increase in TDR. In conclusion, the long QT, short QT, Brugada and catecholaminergic polymorphic VT syndromes are pathologies with very different phenotypes and etiologies, but which share a common final pathway in causing sudden cardiac death. PMID:17586620
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Osadchii, Oleg E
2012-11-01
Flecainide is nonselective Na(+) channel blocker which may also inhibit I(Kr), the rapid component of the delayed rectifier. This study was designed to explore if proarrhythmic responses to flecainide noted in cardiac patients may be partly attributed to abnormal changes in repolarization and refractoriness. Monophasic action potential duration (APD) and effective refractory periods (ERP) were assessed at distinct epicardial and endocardial sites along with volume-conducted ECG recordings in isolated perfused guinea-pig heart preparations. Flecainide was found to prolong ventricular repolarization, with effect being greater at the left ventricular compared with the right ventricular epicardium. This change translated to reversal of the normal right ventricular-to-left ventricular transepicardial APD difference determined before drug infusion. An inverse correlation between local epicardial APD and corresponding activation time values seen at baseline was eliminated in flecainide-treated hearts, indicating the activation-to-repolarization uncoupling. Over transmural plane, flecainide produced a greater ERP lengthening at endocardium than epicardium, thus markedly increasing ERP dispersion across ventricular wall. Spontaneous short-lasting episodes of monomorphic ventricular tachycardia were observed in 45% of heart preparations upon flecainide infusion. In conclusion, in nonischemic guinea-pig heart, flecainide-induced proarrhythmia may be partly attributed to abnormal spatial gradients in repolarization and refractoriness and impaired transepicardial activation-to-repolarization coupling.
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Carro, Jesús; Rodríguez, José Félix; Laguna, Pablo; Pueyo, Esther
2011-11-13
In this study, several modifications were introduced to a recently proposed human ventricular action potential (AP) model so as to render it suitable for the study of ventricular arrhythmias. These modifications were driven by new sets of experimental data available from the literature and the analysis of several well-established cellular arrhythmic risk biomarkers, namely AP duration at 90 per cent repolarization (APD(90)), AP triangulation, calcium dynamics, restitution properties, APD(90) adaptation to abrupt heart rate changes, and rate dependence of intracellular sodium and calcium concentrations. The proposed methodology represents a novel framework for the development of cardiac cell models. Five stimulation protocols were applied to the original model and the ventricular AP model developed here to compute the described arrhythmic risk biomarkers. In addition, those models were tested in a one-dimensional fibre in which hyperkalaemia was simulated by increasing the extracellular potassium concentration, [K(+)](o). The effective refractory period (ERP), conduction velocity (CV) and the occurrence of APD alternans were investigated. Results show that modifications improved model behaviour as verified by: (i) AP triangulation well within experimental limits (the difference between APD at 50 and 90 per cent repolarization being 78.1 ms); (ii) APD(90) rate adaptation dynamics characterized by fast and slow time constants within physiological ranges (10.1 and 105.9 s); and (iii) maximum S1S2 restitution slope in accordance with experimental data (S(S1S2)=1.0). In simulated tissues under hyperkalaemic conditions, APD(90) progressively shortened with the degree of hyperkalaemia, whereas ERP increased once a threshold in [K(+)](o) was reached ([K(+)](o)≈6 mM). CV decreased with [K(+)](o), and conduction was blocked for [K(+)](o)>10.4 mM. APD(90) alternans were observed for [K(+)](o)>9.8 mM. Those results adequately reproduce experimental observations. This study demonstrated the value of basing the development of AP models on the computation of arrhythmic risk biomarkers, as opposed to joining together independently derived ion channel descriptions to produce a whole-cell AP model, with the new framework providing a better picture of the model performance under a variety of stimulation conditions. On top of replicating experimental data at single-cell level, the model developed here was able to predict the occurrence of APD(90) alternans and areas of conduction block associated with high [K(+)](o) in tissue, which is of relevance for the investigation of the arrhythmogenic substrate in ischaemic hearts.
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Roberts, Byron N.; Christini, David J.
2012-01-01
Myocardial ischemia-reperfusion (IR) injury represents a constellation of pathological processes that occur when ischemic myocardium experiences a restoration of perfusion. Reentrant arrhythmias, which represent a particularly lethal manifestation of IR injury, can result when ischemic tissue exhibits decreased excitability and/or changes of action potential duration (APD), conditions that precipitate unidirectional conduction block. Many of the cellular components that are involved with IR injury are modulated by pH and/or phosphometabolites such as ATP and phosphocreatine (PCr), all of which can be manipulated in vivo and potentially in the clinical setting. Using a mathematical model of the cardiomyocyte that we previously developed to study ischemia and reperfusion, we performed a series of simulations with the aim of determining whether pH- or phosphometabolite-related processes play a more significant role in generating changes in excitability and action potential morphology that are associated with the development of reentry. In our simulations, persistent shortening of APD, action potential amplitude (APA), and depolarization of the resting membrane potential were more severe when ATP and PCr availability were suppressed during reperfusion than when extracellular pH recovery was inhibited. Reduced phosphometabolite availability and pH recovery affected multiple ion channels and exchangers. Some of these effects were the result of direct modulation by phosphometabolites and/or acidosis, while others resulted from elevated sodium and calcium loads during reperfusion. In addition, increasing ATP and PCr availability during reperfusion was more beneficial in terms of increasing APD and APA than was increasing the amount of pH recovery. Together, these results suggest that therapies directed at increasing ATP and/or PCr availability during reperfusion may be more beneficial than perturbing pH recovery with regard to mitigating action potential changes that increase the likelihood of reentrant arrhythmias. PMID:23144801
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Spatiotemporal differentiation in auditory and motor regions during auditory phoneme discrimination.
Aerts, Annelies; Strobbe, Gregor; van Mierlo, Pieter; Hartsuiker, Robert J; Corthals, Paul; Santens, Patrick; De Letter, Miet
2017-06-01
Auditory phoneme discrimination (APD) is supported by both auditory and motor regions through a sensorimotor interface embedded in a fronto-temporo-parietal cortical network. However, the specific spatiotemporal organization of this network during APD with respect to different types of phonemic contrasts is still unclear. Here, we use source reconstruction, applied to event-related potentials in a group of 47 participants, to uncover a potential spatiotemporal differentiation in these brain regions during a passive and active APD task with respect to place of articulation (PoA), voicing and manner of articulation (MoA). Results demonstrate that in an early stage (50-110 ms), auditory, motor and sensorimotor regions elicit more activation during the passive and active APD task with MoA and active APD task with voicing compared to PoA. In a later stage (130-175 ms), the same auditory and motor regions elicit more activation during the APD task with PoA compared to MoA and voicing, yet only in the active condition, implying important timing differences. Degree of attention influences a frontal network during the APD task with PoA, whereas auditory regions are more affected during the APD task with MoA and voicing. Based on these findings, it can be carefully suggested that APD is supported by the integration of early activation of auditory-acoustic properties in superior temporal regions, more perpetuated for MoA and voicing, and later auditory-to-motor integration in sensorimotor areas, more perpetuated for PoA.
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Undrovinas, Albertas I.; Belardinelli, Luiz; Undrovinas, Nidas A.; Sabbah, Hani N.
2005-01-01
Background Ventricular repolarization and contractile function are frequently abnormal in ventricular myocytes from human failing hearts as well as canine hearts with experimentally induced heart failure (HF). These abnormalities have been attributed to dysfunction involving various steps of the excitation-contraction coupling process, leading to impaired intracellular sodium and calcium homeostasis. We previously reported that the slow inactivating component of the Na+ current (late INa) is augmented in myocytes from failing hearts, and this appears to play a significant role in abnormal ventricular myocytes repolarization and function. We tested the effect of ranolazine, a novel drug being developed to treat angina, on 1) action potential duration (APD), 2) peak transient and late INa (INaT and INaL respectively), 3) early afterdepolarizations (EADs), and 4) twitch contraction (TC) including aftercontractions and contracture. Methods: Myocytes were isolated from the left ventricle of normal dogs and of dogs with chronic HF caused by multiple sequential intracoronary microembolizations. INaT and INaL were recorded using conventional whole-cell patch-clamp techniques. APs were recorded using the β-escin perforated patch-clamp configuration at frequencies of 0.25 and 0.5 Hz. TCs were recorded using an edge movement detector at stimulation frequencies ranging from 0.5 to 2.0 Hz. Results Ranolazine significantly (p < 0.05) and reversibly shortened the APD of myocytes stimulated at either 0.5 or 0.25 Hz in a concentration-dependent manner. At a stimulation frequency of 0.5 Hz, 5, 10 and 20 μM ranolazine shortened the APD90 (APD measured at 90% repolarization) from 516 ± 51 to 304 ± 22, 212 ± 34 and 160 ± 11 ms, respectively, and markedly decreased beat-to-beat variability of APD90, EADs and dispersion of APDs. Ranolazine preferentially blocked INaL relative to INaT in a state-dependent manner; with a ~ 38-fold greater potency against INaL to produce tonic block (IC50 = 6.5 μ M) than INaT (IC50 =294 μM). When we evaluated inactivated state blockade of INaL from the steady-state inactivation mid-potential shift using a theoretical model, ranolazine was found to bind more tightly to the inactivated state than the resting state of the sodium channel underlying INaL, with apparent dissociation constants Kdr=7.47μ M and Kdi=1.71μ M, respectively. TCs of myocytes stimulated at 0.5 Hz were characterized by an initial spike followed by a dome-like aftercontraction, which was observed in75% of myocytes from failing hearts and coincided with the long AP plateau and EADs. Ranolazine at 5, and 10 μM reversibly shortened duration of TCs and abolished the aftercontraction. When the rate of myocyte stimulation was increased from 1.0 to 2.0 Hz, there was a progressive increase in diastolic “tension”, i.e., contracture. Ranolazine at 5, and 10 μM reversibly prevented this frequency-dependent contracture. PMID:16686675
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Colman, Michael A; Aslanidi, Oleg V; Kharche, Sanjay; Boyett, Mark R; Garratt, Clifford; Hancox, Jules C; Zhang, Henggui
2013-01-01
Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche–Ramirez–Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca2+ handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate initiation and maintenance of re-entrant excitation waves. PMID:23732649
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Colman, Michael A; Aslanidi, Oleg V; Kharche, Sanjay; Boyett, Mark R; Garratt, Clifford; Hancox, Jules C; Zhang, Henggui
2013-09-01
Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche-Ramirez-Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca(2+) handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate initiation and maintenance of re-entrant excitation waves.
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Acute amiodarone promotes drift and early termination of spiral wave re-entry.
Nakagawa, Harumichi; Honjo, Haruo; Ishiguro, Yuko S; Yamazaki, Masatoshi; Okuno, Yusuke; Harada, Masahide; Takanari, Hiroki; Sakuma, Ichiro; Kamiya, Kaichiro; Kodama, Itsuo
2010-07-01
Intravenous application of amiodarone is commonly used in the treatment of life-threatening arrhythmias, but the underlying mechanism is not fully understood. The purpose of the present study is to investigate the acute effects of amiodarone on spiral wave (SW) re-entry, the primary organization machinery of ventricular tachycardia/fibrillation (VT/VF), in comparison with lidocaine. A two-dimensional ventricular myocardial layer was obtained from 24 Langendorff-perfused rabbit hearts, and epicardial excitations were analyzed by high-resolution optical mapping. During basic stimulation, amiodarone (5 microM) caused prolongation of action potential duration (APD) by 5.6%-9.1%, whereas lidocaine (15 microM) caused APD shortening by 5.0%-6.4%. Amiodarone and lidocaine reduced conduction velocity similarly. Ventricular tachycardias induced by DC stimulation in the presence of amiodarone were of shorter duration (sustained-VTs >30 s/total VTs: 2/58, amiodarone vs 13/52, control), whereas those with lidocaine were of longer duration (22/73, lidocaine vs 14/58, control). Amiodarone caused prolongation of VT cycle length and destabilization of SW re-entry, which is characterized by marked prolongation of functional block lines, frequent wavefront-tail interactions near the rotation center, and considerable drift, leading to its early annihilation via collision with anatomical boundaries. Spiral wave re-entry in the presence of lidocaine was more stabilized than in control. In the anisotropic ventricular myocardium, amiodarone destabilizes SW re-entry facilitating its early termination. Lidocaine, in contrast, stabilizes SW re-entry resulting in its persistence.
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Wu, Jianjun; Jamil, Mohd Fadzly Amar; Tan, Mei Lan; Adenan, Mohd Ilham; Wong, Philip; Shim, Winston
2014-01-01
Introduction Mitragynine is a major bioactive compound of Kratom, which is derived from the leave extracts of Mitragyna speciosa Korth or Mitragyna speciosa (M. speciosa), a medicinal plant from South East Asia used legally in many countries as stimulant with opioid-like effects for the treatment of chronic pain and opioid-withdrawal symptoms. Fatal incidents with Mitragynine have been associated with cardiac arrest. In this study, we determined the cardiotoxicity of Mitragynine and other chemical constituents isolated using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and Results The rapid delayed rectifier potassium current (I Kr), L-type Ca2+ current (I Ca,L) and action potential duration (APD) were measured by whole cell patch-clamp. The expression of KCNH2 and cytotoxicity was determined by real-time PCR and Caspase activity measurements. After significant I Kr suppression by Mitragynine (10 µM) was confirmed in hERG-HEK cells, we systematically examined the effects of Mitragynine and other chemical constituents in hiPSC-CMs. Mitragynine, Paynantheine, Speciogynine and Speciociliatine, dosage-dependently (0.1∼100 µM) suppressed I Kr in hiPSC-CMs by 67% ∼84% with IC50 ranged from 0.91 to 2.47 µM. Moreover, Mitragynine (10 µM) significantly prolonged APD at 50 and 90% repolarization (APD50 and APD90) (439.0±11.6 vs. 585.2±45.5 ms and 536.0±22.6 vs. 705.9±46.1 ms, respectively) and induced arrhythmia, without altering the L-type Ca2+ current. Neither the expression,and intracellular distribution of KCNH2/Kv11.1, nor the Caspase 3 activity were significantly affected by Mitragynine. Conclusions Our study indicates that Mitragynine and its analogues may potentiate Torsade de Pointes through inhibition of I Kr in human cardiomyocytes. PMID:25535742
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Effect of clebopride, antidopaminergic gastrointestinal prokinetics, on cardiac repolarization.
Kim, Ki-Suk; Shin, Won-Ho; Park, Sang-joon; Kim, Eun-Joo
2007-01-01
The inhibition of the potassium current I(Kr) and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. In this study, the authors investigated the cardiac electrophysiological effects of clebopride, a class of antidopaminergic gastrointestinal prokinetic, that has been reported to prolong the QT interval by using the conventional microelectrode recording techniques in isolated rabbit Purkinje fiber and whole-cell patch clamp techniques in human ether-à-go-go-related gene (hERG)-stably transfected Chinese hamster ovarian (CHO) cells. Clebopride at 10 microM significantly decreased the Vmax of phase 0 depolarization (p < .05) and significantly prolonged the action potential duration at 90% repolarization (APD90) (p < .01), whereas the action potential duration at 50% repolarization (APD50) was not prolonged. For hERG potassium channel currents, the IC50 value was 0.62 +/- 0.30 microM. Clebopride was found to have no effect on sodium channel currents. When these results were compared with Cmax (1.02 nM) of clinical dosage (1 mg, [p.o.]), it can be suggested that clebopride is safe at the clinical dosage of 1 mg from the electrophysiological aspect. These findings indicate that clebopride, an antidopaminergic gastrointestinal prokinetic drug, may provide a sufficient "safety factor" in terms of the electrophysiological threshold concentration. But, in a supratherapeutic concentration that might possibly be encountered during overdose or impaired metabolism, clebopride may have torsadogenic potency.
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Murphy, Shannon R.; Wang, Lianguo; Wang, Zhen; Domondon, Philip; Lang, Di; Habecker, Beth A.; Myles, Rachel C.; Ripplinger, Crystal M.
2017-01-01
β-adrenergic receptor (β-AR) blockers may be administered during acute myocardial infarction (MI), as they reduce energy demand through negative chronotropic and inotropic effects and prevent ischemia-induced arrhythmogenesis. However, the direct effects of β-AR blockers on ventricular electrophysiology and intracellular Ca2+ handling during ischemia remain unknown. Using optical mapping of transmembrane potential (with RH237) and sarcoplasmic reticulum (SR) Ca2+ (with the low-affinity indicator Fluo-5N AM), the effects of 15 min of regional ischemia were assessed in isolated rabbit hearts (n = 19). The impact of β-AR inhibition on isolated hearts was assessed by pre-treatment with 100 nM propranolol (Prop) prior to ischemia (n = 7). To control for chronotropy and inotropy, hearts were continuously paced at 3.3 Hz and contraction was inhibited with 20 μM blebbistatin. Untreated ischemic hearts displayed prototypical shortening of action potential duration (APD80) in the ischemic zone (IZ) compared to the non-ischemic zone (NI) at 10 and 15 min ischemia, whereas APD shortening was prevented with Prop. Untreated ischemic hearts also displayed significant changes in SR Ca2+ handling in the IZ, including prolongation of SR Ca2+ reuptake and SR Ca2+ alternans, which were prevented with Prop pre-treatment. At 5 min ischemia, Prop pre-treated hearts also showed larger SR Ca2+ release amplitude in the IZ compared to untreated hearts. These results suggest that even when controlling for chronotropic and inotropic effects, β-AR inhibition has a favorable effect during acute regional ischemia via direct effects on APD and Ca2+ handling. PMID:28894423
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Trieschmann, Jan; Bettin, Daniel; Haustein, Moritz; Köster, Annette; Molcanyi, Marek; Halbach, Marcel; Hanna, Mira; Fouad, Mariam; Brockmeier, Konrad; Hescheler, Jürgen; Pfannkuche, Kurt; Hannes, Tobias
2016-01-01
Transplantation of stem cell-derived cardiomyocytes is one of the most promising therapeutic approaches after myocardial infarction, as loss of cardiomyocytes is virtually irreversible by endogenous repair mechanisms. In myocardial scars, transplanted cardiomyocytes will be in immediate contact with cardiac fibroblasts. While it is well documented how the electrophysiology of neonatal cardiomyocytes is modulated by cardiac fibroblasts of the same developmental stage, it is unknown how adult cardiac fibroblasts (aCFs) affect the function of embryonic stem cell-derived cardiomyocytes (ESC-CMs). To investigate the effects of aCFs on ESC-CM electrophysiology, we performed extra- and intracellular recordings of murine aCF-ESC-CM cocultures. We observed that spontaneous beating behaviour was highly irregular in aCF-ESC-CM cocultures compared to cocultures with mesenchymal stem cells (coefficient of variation of the interspike interval: 40.5 ± 15.2% versus 9.3 ± 2.0%, p = 0.008) and that action potential amplitude and maximal upstroke velocity (V max) were reduced (amplitude: 52.3 ± 1.7 mV versus 65.1 ± 1.5 mV, V max: 7.0 ± 1.0 V/s versus 36.5 ± 5.3 V/s), while action potential duration (APD) was prolonged (APD50: 25.6 ± 1.0 ms versus 16.8 ± 1.9 ms, p < 0.001; APD90: 52.2 ± 1.5 ms versus 43.3 ± 3.3 ms, p < 0.01) compared to controls. Similar changes could be induced by aCF-conditioned medium. We conclude that the presence of aCFs changes automaticity and induces potentially proarrhythmic changes of ESC-CM electrophysiology. PMID:26880949
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Trieschmann, Jan; Bettin, Daniel; Haustein, Moritz; Köster, Annette; Molcanyi, Marek; Halbach, Marcel; Hanna, Mira; Fouad, Mariam; Brockmeier, Konrad; Hescheler, Jürgen; Pfannkuche, Kurt; Hannes, Tobias
2016-01-01
Transplantation of stem cell-derived cardiomyocytes is one of the most promising therapeutic approaches after myocardial infarction, as loss of cardiomyocytes is virtually irreversible by endogenous repair mechanisms. In myocardial scars, transplanted cardiomyocytes will be in immediate contact with cardiac fibroblasts. While it is well documented how the electrophysiology of neonatal cardiomyocytes is modulated by cardiac fibroblasts of the same developmental stage, it is unknown how adult cardiac fibroblasts (aCFs) affect the function of embryonic stem cell-derived cardiomyocytes (ESC-CMs). To investigate the effects of aCFs on ESC-CM electrophysiology, we performed extra- and intracellular recordings of murine aCF-ESC-CM cocultures. We observed that spontaneous beating behaviour was highly irregular in aCF-ESC-CM cocultures compared to cocultures with mesenchymal stem cells (coefficient of variation of the interspike interval: 40.5 ± 15.2% versus 9.3 ± 2.0%, p = 0.008) and that action potential amplitude and maximal upstroke velocity (V max) were reduced (amplitude: 52.3 ± 1.7 mV versus 65.1 ± 1.5 mV, V max: 7.0 ± 1.0 V/s versus 36.5 ± 5.3 V/s), while action potential duration (APD) was prolonged (APD50: 25.6 ± 1.0 ms versus 16.8 ± 1.9 ms, p < 0.001; APD90: 52.2 ± 1.5 ms versus 43.3 ± 3.3 ms, p < 0.01) compared to controls. Similar changes could be induced by aCF-conditioned medium. We conclude that the presence of aCFs changes automaticity and induces potentially proarrhythmic changes of ESC-CM electrophysiology.
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Frommeyer, Gerrit; Brücher, Benedict; von der Ahe, Henning; Kaese, Sven; Dechering, Dirk G; Kochhäuser, Simon; Bogossian, Harilaos; Milberg, Peter; Eckardt, Lars
2016-10-05
In several case reports proarrhythmic effects of citalopram and escitalopram have been reported. Systematic analyses on prorarrhythmic effects of these drugs are not yet available. The aim of the present study was to investigate if application of citalopram, escitalopram or haloperidol provokes polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In isolated rabbit hearts monophasic action potentials and ECG showed a significant QT-prolongation after application of citalopram (2µM: +47ms, 4µM: +56ms, P<0.05) accompanied by an increase of action potential duration (APD) but not dispersion of repolarization. Reduced potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EAD) in 2 of 12 hearts but no polymorphic ventricular tachycardia (pVT). Application of escitalopram also increased QT-interval (2µM: +3ms, 4µM: +30ms, P<0.05) and APD without effects on dispersion. 3 of 10 hearts showed EAD and pVT in 2 of 10 hearts (32 episodes). The results were compared to 12 rabbits treated with haloperidol which led to an increase in QT-interval (1µM:+62ms; 2µM:+96ms; P<0.01), APD and dispersion (1µM:+15ms, 2µM:+40ms; P<0.01) and induced EAD in all 12 and pVT in 10 of 12 hearts (152 episodes). Citalopram and escitalopram demonstrated a rather safe electrophysiologic profile despite significant QT prolongation. In contrast, haloperidol led to significant increase of dispersion of repolarization while this parameter remained stable under the influence of citalopram or escitalopram. These results imply that application of citalopram or escitalopram is not as proarrhythmic as some case reports might suggest while haloperidol is torsadogenic. Copyright © 2016 Elsevier B.V. All rights reserved.
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Luo, Wenqi; Jia, Yixin; Zheng, Shuai; Li, Yan; Han, Jie; Meng, Xu
2017-01-01
Acute cardiac rejection contributes to the changes in the electrophysiological properties of grafted hearts. However, the electrophysiological changes of cardiomyocytes during acute cardiac rejection are still unknown. An understanding of the electrophysiological mechanisms of cardiomyocytes could improve the diagnosis and treatment of acute cardiac rejection. So it is important to characterize the changes in the action potential ( AP ) and the transient outward potassium current ( I to ) in cardiomyocytes during acute cardiac rejection. Heterotopic heart transplantation was performed in allogeneic [Brown Norway (BN)-to-Lewis] and isogeneic (BN-to-BN) rats. Twenty models were established in each group. Ten recipients were sacrificed at the 2nd day and the other ten recipients were sacrificed at the 4 th day after the operation in each group. Histopathological examinations of the grafted hearts were performed in half of the recipients in each group randomly. The other half of the grafted hearts were excised rapidly and enzymatically dissociated to obtain single cardiomyocytes. The AP and I to current were recorded using the whole cell patch-clamp technique. Forty grafted hearts were successfully harvested and used in experiments. Histologic examination showed mild rejection at the 2 nd day and moderate rejection at the 4 th day in the allogeneic group after cardiac transplantation, while no evidence of histologic lesions of rejection were observed in the isogeneic group. Compared with the isogeneic group, the action potential duration ( APD ) of cardiomyocytes in the allogeneic group was significantly prolonged ( APD 90 was 49.28±5.621 mV in the isogeneic group and 88.08±6.445 mV in the allogeneic group at the 2 nd day, P=0.0016; APD 90 was 59.34±5.183 mV in the isogeneic group and 104.0±9.523 mV in the allogeneic group at the 4 th day, P=0.0064). The current density of I to was significantly decreased at the 4 th day after cardiac transplantation. The APD of cardiomyocytes was significantly prolonged during acute cardiac rejection in rats, which might be partly attributed to decreased current densities of I to .
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NASA Astrophysics Data System (ADS)
Comlekoglu, T.; Weinberg, S. H.
2017-09-01
Cardiac memory is the dependence of electrical activity on the prior history of one or more system state variables, including transmembrane potential (Vm), ionic current gating, and ion concentrations. While prior work has represented memory either phenomenologically or with biophysical detail, in this study, we consider an intermediate approach of a minimal three-variable cardiomyocyte model, modified with fractional-order dynamics, i.e., a differential equation of order between 0 and 1, to account for history-dependence. Memory is represented via both capacitive memory, due to fractional-order Vm dynamics, that arises due to non-ideal behavior of membrane capacitance; and ionic current gating memory, due to fractional-order gating variable dynamics, that arises due to gating history-dependence. We perform simulations for varying Vm and gating variable fractional-orders and pacing cycle length and measure action potential duration (APD) and incidence of alternans, loss of capture, and spontaneous activity. In the absence of ionic current gating memory, we find that capacitive memory, i.e., decreased Vm fractional-order, typically shortens APD, suppresses alternans, and decreases the minimum cycle length (MCL) for loss of capture. However, in the presence of ionic current gating memory, capacitive memory can prolong APD, promote alternans, and increase MCL. Further, we find that reduced Vm fractional order (typically less than 0.75) can drive phase 4 depolarizations that promote spontaneous activity. Collectively, our results demonstrate that memory reproduced by a fractional-order model can play a role in alternans formation and pacemaking, and in general, can greatly increase the range of electrophysiological characteristics exhibited by a minimal model.
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Choi, Eue-Keun; Chang, Po-Cheng; Lee, Young-Soo; Lin, Shien-Fong; Zhu, Wuqiang; Maruyama, Mitsunori; Fishbein, Michael C.; Chen, Zhenhui; der Lohe, Michael Rubart-von; Field, Loren J.; Chen, Peng-Sheng
2013-01-01
Background Calcium transient triggered firing (CTTF) is induced by large intracellular calcium (Cai) transient and short action potential duration (APD). We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1). Methods and Results MHC-TGFcys33ser Tx mice develop atrial fibrosis because of elevated levels of TGF-β1. We studied membrane potential and Cai transients of isolated superfused atria from Tx and wild-type (Wt) littermates. Short APD and persistently elevated Cai transients promoted spontaneous repetitive EADs, triggered activity and spontaneous AF after cessation of burst pacing in Tx but not Wt atria (39% vs. 0%, P=0.008). We were able to map optically 4 episodes of spontaneous AF re-initiation. All first and second beats of spontaneous AF originated from the right atrium (4/4, 100%), which is more severely fibrotic than the left atrium. Ryanodine and thapsigargin inhibited spontaneous re-initiation of AF in all 7 Tx atria tested. Western blotting showed no significant changes of calsequestrin or sarco/endoplasmic reticulum Ca2+-ATPase 2a. Conclusions Spontaneous AF may occur in the Tx atrium because of CTTF, characterized by APD shortening, prolonged Cai transient, EAD and triggered activity. Inhibition of Ca2+ release from the sarcoplasmic reticulum suppressed spontaneous AF. Our results indicate that CTTF is an important arrhythmogenic mechanism in TGF-β1 Tx atria. PMID:22447020
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Park, Eunjung; Gintant, Gary A; Bi, Daoqin; Kozeli, Devi; Pettit, Syril D; Skinner, Matthew; Willard, James; Wisialowski, Todd; Koerner, John; Valentin, Jean‐Pierre
2018-01-01
Background and Purpose Translation of non‐clinical markers of delayed ventricular repolarization to clinical prolongation of the QT interval corrected for heart rate (QTc) (a biomarker for torsades de pointes proarrhythmia) remains an issue in drug discovery and regulatory evaluations. We retrospectively analysed 150 drug applications in a US Food and Drug Administration database to determine the utility of established non‐clinical in vitro IKr current human ether‐à‐go‐go‐related gene (hERG), action potential duration (APD) and in vivo (QTc) repolarization assays to detect and predict clinical QTc prolongation. Experimental Approach The predictive performance of three non‐clinical assays was compared with clinical thorough QT study outcomes based on free clinical plasma drug concentrations using sensitivity and specificity, receiver operating characteristic (ROC) curves, positive (PPVs) and negative predictive values (NPVs) and likelihood ratios (LRs). Key Results Non‐clinical assays demonstrated robust specificity (high true negative rate) but poor sensitivity (low true positive rate) for clinical QTc prolongation at low‐intermediate (1×–30×) clinical exposure multiples. The QTc assay provided the most robust PPVs and NPVs (ability to predict clinical QTc prolongation). ROC curves (overall test accuracy) and LRs (ability to influence post‐test probabilities) demonstrated overall marginal performance for hERG and QTc assays (best at 30× exposures), while the APD assay demonstrated minimal value. Conclusions and Implications The predictive value of hERG, APD and QTc assays varies, with drug concentrations strongly affecting translational performance. While useful in guiding preclinical candidates without clinical QT prolongation, hERG and QTc repolarization assays provide greater value compared with the APD assay. PMID:29181850
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Ventricular stimulus site influences dynamic dispersion of repolarization in the intact human heart
Orini, Michele; Simon, Ron B.; Providência, Rui; Khan, Fakhar Z.; Segal, Oliver R.; Babu, Girish G.; Bradley, Richard; Rowland, Edward; Ahsan, Syed; Chow, Anthony W.; Lowe, Martin D.; Taggart, Peter
2016-01-01
The spatial variation in restitution properties in relation to varying stimulus site is poorly defined. This study aimed to investigate the effect of varying stimulus site on apicobasal and transmural activation time (AT), action potential duration (APD) and repolarization time (RT) during restitution studies in the intact human heart. Ten patients with structurally normal hearts, undergoing clinical electrophysiology studies, were enrolled. Decapolar catheters were placed apex to base in the endocardial right ventricle (RVendo) and left ventricle (LVendo), and an LV branch of the coronary sinus (LVepi) for transmural recording. S1–S2 restitution protocols were performed pacing RVendo apex, LVendo base, and LVepi base. Overall, 725 restitution curves were analyzed, 74% of slopes had a maximum slope of activation recovery interval (ARI) restitution (Smax) > 1 (P < 0.001); mean Smax = 1.76. APD was shorter in the LVepi compared with LVendo, regardless of pacing site (30-ms difference during RVendo pacing, 25-ms during LVendo, and 48-ms during LVepi; 50th quantile, P < 0.01). Basal LVepi pacing resulted in a significant transmural gradient of RT (77 ms, 50th quantile: P < 0.01), due to loss of negative transmural AT-APD coupling (mean slope 0.63 ± 0.3). No significant transmural gradient in RT was demonstrated during endocardial RV or LV pacing, with preserved negative transmural AT-APD coupling (mean slope −1.36 ± 1.9 and −0.71 ± 0.4, respectively). Steep ARI restitution slopes predominate in the normal ventricle and dynamic ARI; RT gradients exist that are modulated by the site of activation. Epicardial stimulation to initiate ventricular activation promotes significant transmural gradients of repolarization that could be proarrhythmic. PMID:27371682
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Hannes, Tobias; Wolff, Marie; Doss, Michael Xavier; Pfannkuche, Kurt; Haustein, Moritz; Müller-Ehmsen, Jochen; Sachinidis, Agapios; Hescheler, Jürgen; Khalil, Markus; Halbach, Marcel
2015-01-01
Modelling of cardiac development, physiology and pharmacology by differentiation of embryonic stem cells (ESCs) requires comparability of cardiac differentiation between different ESC lines. To investigate whether the outcome of cardiac differentiation is consistent between different ESC lines, we compared electrophysiological properties of ESC-derived cardiomyocytes (ESC-CMs) of different murine ESC lines. Two wild-type (D3 and R1) and two transgenic ESC lines (D3/aPIG44 and CGR8/AMPIGX-7) were differentiated under identical culture conditions. The transgenic cell lines expressed enhanced green fluorescent protein (eGFP) and puromycin-N-acetyltransferase under control of the cardiac specific α-myosin heavy chain (αMHC) promoter. Action potentials (APs) were recorded using sharp electrodes and multielectrode arrays in beating clusters of ESC-CMs. Spontaneous AP frequency and AP duration (APD) as well as maximal upstroke velocity differed markedly between unpurified CMs of the four ESC lines. APD heterogeneity was negligible in D3/aPIG44, moderate in D3 and R1 and extensive in CGR8/AMPIGX-7. Interspike intervals calculated from long-term recordings showed a high degree of variability within and between recordings in CGR8/AMPIGX-7, but not in D3/aPIG44. Purification of the αMHC+ population by puromycin treatment posed only minor changes to APD in D3/aPIG44, but significantly shortened APD in CGR8/AMPIGX-7. Electrophysiological properties of ESC-CMs are strongly cell line-dependent and can be influenced by purification of cardiomyocytes by antibiotic selection. Thus, conclusions on cardiac development, physiology and pharmacology derived from single stem cell lines have to be interpreted carefully. © 2015 S. Karger AG, Basel.
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Tisdale, James E; Allen, Matthew R; Overholser, Brian R; Jaynes, Heather A; Kovacs, Richard J
2015-06-01
Our objective was to determine effects of zoledronic acid (ZA) on atrial electrophysiological parameters and electrocardiographic measurements. Ex vivo perfusion study: Isolated guinea pig hearts were perfused with modified Krebs-Henseleit (K-H) buffer with or without ZA 0.07 mg/kg/L (each n = 6). In ZA-perfused hearts, atrial action potential at 90% repolarization (APD90 ) decreased more from baseline than in controls (-23.2% ± -5.1% vs. -2.1% ± -8.1%, P < 0 .0001), as did APD30 (-28.8% ± -3.8% vs. -2.1% ± -2.1%, P < 0.0001). In vivo dose-response study: Guinea pigs underwent intraperitoneal injections every 2 weeks in 1 of 4 groups (each n = 8): ZA 0.007 mg/kg (low-dose), ZA 0.07 mg/kg (medium-dose), ZA 0.7 mg/kg (high-dose), or placebo. Hearts were excised at 8 weeks and perfused with modified K-H. Atrial effective refractory period (ERP) was lower with medium- and high-dose ZA versus placebo (P = 0.004). Atrial APD30 was lower with high-dose ZA versus placebo, low and medium doses (P < 0.001). Canine ECG study: Mature female beagles received intravenous ZA 0.067 mg/kg or saline (placebo; each n = 6) every 2 weeks for 12 weeks. P wave dispersion was greater in the ZA group (7.7 ± 3.7 vs. 3.4 ± 2.6 ms, P = 0.04). There were no significant differences in P wave index, maximum or minimum P wave duration, or PR interval. ZA shortens left atrial APD and ERP and increases P wave dispersion. © 2015 Wiley Periodicals, Inc.
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Uemura, Kazunori; Inagaki, Masashi; Zheng, Can; Kawada, Toru; Li, Meihua; Fukumitsu, Masafumi; Sugimachi, Masaru
2017-04-01
Ivabradine, a bradycardic agent, has been shown to stably reduce patient's heart rate (HR) in the setting of acute cardiac care. However, an association between atrial fibrillation (AF) risk and acute ivabradine treatment remains a controversial clinical issue, and has not been thoroughly investigated. Bradycardia and abnormal atrial refractoriness induced by ivabradine treatment may enhance vulnerability to AF induction, especially when vagal nerve is concurrently activated. We aimed to experimentally investigate the effects of acute ivabradine treatment with/without concurrent vagal activation on AF inducibility. In 16 anesthetized dogs, cervical vagal nerves were prepared for electrical stimulation (VS). AF induction rate (AFIR) was determined by atrial burst pacing. HR, atrial action potential duration (APD), atrial effective refractory period (ERP), and AFIR were obtained consecutively at baseline, during delivery of VS (VS alone), after intravenous injection of ivabradine 0.5 mg/kg (n = 8, ivabradine group) or saline (n = 8, saline group), and again during VS delivery (drug+VS). In the ivabradine group, ivabradine alone significantly lowered HR compared to baseline, while ivabradine+VS significantly lowered HR compared to VS alone. Contrary to expectations, there were no significant differences in trends of APD, temporal dispersion of APD, ERP, and AFIR between ivabradine and saline groups. Irrespective of whether ivabradine or saline was injected, VS significantly shortened APD and ERP, and increased AFIR. Interestingly, although bradycardia in response to ivabradine injection was more intense than that to VS alone, AFIR was significantly lower after ivabradine injection than during VS alone. We conclude that, despite its intense bradycardic effect, acute ivabradine treatment does not increase AF inducibility irrespective of underlying vagal activity. This study may constitute support for the safety of using ivabradine in the setting of acute cardiac care.
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Huang, Bing; Yu, Lilei; He, Bo; Lu, Zhibing; Wang, Songyun; He, Wenbo; Yang, Kang; Liao, Kai; Zhang, Ling; Jiang, Hong
2014-11-01
Recently, a beneficial effect of renal sympathetic denervation (RSD) has been seen in patients with ventricular electrical storm. However, the effect of RSD on ventricular electrophysiology remains unclear. Thirty-three mongrel dogs were included in the present study. Renal sympathetic denervation was performed by radiofrequency ablation of the adventitial surface of the renal artery. In group 1 (n = 8), programmed stimulation was performed before and after RSD to determine the ventricular effective refractory period (ERP) and action potential duration (APD) restitution properties. The same parameters were measured in five other animals that underwent sham RSD to serve as controls. In group 2 (n = 10), acute myocardial ischaemia (AMI) was induced by ligating the proximal left anterior descending coronary artery after the performance of RSD, and the incidence of ventricular arrhythmia (VA) was calculated during 1 h of recording. In another 10 dogs (group 3), AMI was induced and VA was measured with sham RSD. In group 1, RSD significantly prolonged ventricular ERP and APD, reduced the maximal slope (Smax) of the restitution curve and suppressed APD alternans at each site. Renal sympathetic denervation also significantly decreased the spatial dispersion of ERP, APD and Smax. In the five control animals, no significant electrophysiological change was detected after sham RSD. The occurrence of spontaneous VA during 1 h of AMI in group 2 was significantly lower than that in group 3. These data suggest that RSD stabilizes ventricular electrophysiological properties in normal hearts and reduces the occurrence of VA in hearts experiencing AMI. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.
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Osadchii, O E
2012-08-01
Endocardial pacing instituted to treat symptomatic bradycardia may nevertheless promote tachyarrhythmia in some pacemaker-implanted patients. We sought to determine the contributing electrophysiological mechanisms. Left ventricular (LV) monophasic action potential duration (APD(90)) and effective refractory periods were determined in perfused guinea-pig hearts along with volume-conducted ECG recordings during epicardial and endocardial stimulations. Consistent with electrotonic modulation of repolarization, APD(90) at a given (either epicardial or endocardial) recording site tended to be longer while pacing from the ipsilateral LV site as compared to stimulations applied at the opposite side of ventricular wall. As a result, the intrinsic transmural repolarization gradient was amplified during endocardial pacing while being significantly reduced upon epicardial stimulations. The maximum slope of APD(90) restitution was greater upon endocardial than epicardial pacing. The excitability was found to recur at earlier repolarization time point at endocardium than epicardium, thereby contributing to increased endocardial critical intervals for re-excitation. Premature extrasystolic beats could have been elicited at shorter coupling stimulation intervals and propagated with greater transmural conduction delay upon endocardial than epicardial stimulations. Endocardial site exhibited lower ventricular fibrillation thresholds and greater inducibility of tachyarrhythmia upon extrasystolic stimulations as compared to epicardium. Arrhythmic susceptibility in guinea-pig heart is greater during endocardial than epicardial pacing because of greater transmural APD(90) dispersion, steeper electrical restitution slopes, greater critical intervals for LV re-excitation and slower transmural conduction of the earliest premature ectopic beats. Further studies are warranted to determine whether these effects may contribute to proarrhythmia in paced human patients. © 2012 The Author Acta Physiologica © 2012 Scandinavian Physiological Society.
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Jans, Danny; Callewaert, Geert; Krylychkina, Olga; Hoffman, Luis; Gullo, Francesco; Prodanov, Dimiter; Braeken, Dries
2017-09-01
Drug-induced cardiotoxicity poses a negative impact on public health and drug development. Cardiac safety pharmacology issues urged for the preclinical assessment of drug-induced ventricular arrhythmia leading to the design of several in vitro electrophysiological screening assays. In general, patch clamp systems allow for intracellular recordings, while multi-electrode array (MEA) technology detect extracellular activity. Here, we demonstrate a complementary metal oxide semiconductor (CMOS)-based MEA system as a reliable platform for non-invasive, long-term intracellular recording of cardiac action potentials at high resolution. Quinidine (8 concentrations from 10 -7 to 2.10 -5 M) and verapamil (7 concentrations from 10 -11 to 10 -5 M) were tested for dose-dependent responses in a network of cardiomyocytes. Electrophysiological parameters, such as the action potential duration (APD), rates of depolarization and repolarization and beating frequency were assessed. In hiPSC, quinidine prolonged APD with EC 50 of 2.2·10 -6 M. Further analysis indicated a multifactorial action potential prolongation by quinidine: (1) decreasing fast repolarization with IC 50 of 1.1·10 -6 M; (2) reducing maximum upstroke velocity with IC 50 of 2.6·10 -6 M; and (3) suppressing spontaneous activity with EC 50 of 3.8·10 -6 M. In rat neonatal cardiomyocytes, verapamil blocked spontaneous activity with EC 50 of 5.3·10 -8 M and prolonged the APD with EC 50 of 2.5·10 -8 M. Verapamil reduced rates of fast depolarization and repolarization with IC 50 s of 1.8 and 2.2·10 -7 M, respectively. In conclusion, the proposed action potential-based MEA platform offers high quality and stable long-term recordings with high information content allowing to characterize multi-ion channel blocking drugs. We anticipate application of the system as a screening platform to efficiently and cost-effectively test drugs for cardiac safety. Copyright © 2017 Elsevier Inc. All rights reserved.
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Photodiode Preamplifier for Laser Ranging With Weak Signals
NASA Technical Reports Server (NTRS)
Abramovici, Alexander; Chapsky, Jacob
2007-01-01
An improved preamplifier circuit has been designed for processing the output of an avalanche photodiode (APD) that is used in a high-resolution laser ranging system to detect laser pulses returning from a target. The improved circuit stands in contrast to prior such circuits in which the APD output current pulses are made to pass, variously, through wide-band or narrow-band load networks before preamplification. A major disadvantage of the prior wide-band load networks is that they are highly susceptible to noise, which degrades timing resolution. A major disadvantage of the prior narrow-band load networks is that they make it difficult to sample the amplitudes of the narrow laser pulses ordinarily used in ranging. In the improved circuit, a load resistor is connected to the APD output and its value is chosen so that the time constant defined by this resistance and the APD capacitance is large, relative to the duration of a laser pulse. The APD capacitance becomes initially charged by the pulse of current generated by a return laser pulse, so that the rise time of the load-network output is comparable to the duration of the return pulse. Thus, the load-network output is characterized by a fast-rising leading edge, which is necessary for accurate pulse timing. On the other hand, the resistance-capacitance combination constitutes a lowpass filter, which helps to suppress noise. The long time constant causes the load network output pulse to have a long shallow-sloping trailing edge, which makes it easy to sample the amplitude of the return pulse. The output of the load network is fed to a low-noise, wide-band amplifier. The amplifier must be a wide-band one in order to preserve the sharp pulse rise for timing. The suppression of noise and the use of a low-noise amplifier enable the ranging system to detect relatively weak return pulses.
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Yan, Dong; Cheng, Lu-feng; Song, Hong-Yan; Turdi, Subat; Kerram, Parhat
2007-08-01
Overdoses of haloperidol are associated with major ventricular arrhythmias, cardiac conduction block, and sudden death. The aim of this experiment was to study the effect of haloperidol on the action potentials in cardiac Purkinje fibers and papillary muscles under normal and simulated ischemia conditions in rabbits and guinea pigs. Using the standard intracellular microelectrode technique, we examined the effects of haloperidol on the action potential parameters [action potential amplitude (APA), phase 0 maximum upstroke velocity (V(max)), action potential amplitude at 90% of repolarization (APD(90)), and effective refractory period (ERP)] in rabbit cardiac Purkinje fibers and guinea pig cardiac papillary cells, in which both tissues were under simulated ischemic conditions. Under ischemic conditions, different concentrations of haloperidol depressed APA and prolonged APD(90) in a concentration-dependent manner in rabbit Purkinje fibers. Haloperidol (3 micromol/L) significantly depressed APA and prolonged APD(90), and from 1 micromol/L, haloperidol showed significant depression on V(max); ERP was not significantly affected. In guinea pig cardiac papillary muscles, the thresholds of significant reduction in APA, V(max), EPR, and APD(90) were 10, 0.3, 1, and 1 mumol/L, respectively, for haloperidol. Compared with cardiac conductive tissues, papillary muscles were more sensitive to ischemic conditions. Under ischemia, haloperidol prolonged ERP and APD(90) in a concentration-dependent manner and precipitated the decrease in V(max) induced by ischemia. The shortening of ERP and APD(90) in papillary muscle action potentials may be inhibited by haloperidol.
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Uldry, Laurent; Virag, Nathalie; Jacquemet, Vincent; Vesin, Jean-Marc; Kappenberger, Lukas
2010-12-01
While successful termination by pacing of organized atrial tachycardias has been observed in patients, rapid pacing of AF can induce a local capture of the atrial tissue but in general no termination. The purpose of this study was to perform a systematic evaluation of the ability to capture AF by rapid pacing in a biophysical model of the atria with different dynamics in terms of conduction velocity (CV) and action potential duration (APD). Rapid pacing was applied during 30 s at five locations on the atria, for pacing cycle lengths in the range 60-110% of the mean AF cycle length (AFCL(mean)). Local AF capture could be achieved using rapid pacing at pacing sites located distal to major anatomical obstacles. Optimal pacing cycle lengths were found in the range 74-80% AFCL(mean) (capture window width: 14.6 ± 3% AFCL(mean)). An increase/decrease in CV or APD led to a significant shrinking/stretching of the capture window. Capture did not depend on AFCL, but did depend on the atrial substrate as characterized by an estimate of its wavelength, a better capture being achieved at shorter wavelengths. This model-based study suggests that a proper selection of the pacing site and cycle length can influence local capture results and that atrial tissue properties (CV and APD) are determinants of the response to rapid pacing.
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Wu, Ziqi; Kumon, Ronald E; Laughner, Jacob I; Efimov, Igor R; Deng, Cheri X
2015-02-01
To gain better understanding of the detailed mechanisms of high-intensity focused ultrasound (HIFU) ablation for cardiac arrhythmias, we investigated how the cellular electrophysiological (EP) changes were correlated with temperature increases and thermal dose (cumulative equivalent minutes [CEM43]) during HIFU application using Langendorff-perfused rabbit hearts. Employing voltage-sensitive dye di-4-ANEPPS, we measured the EP and temperature during HIFU using simultaneous optical mapping and infrared imaging. Both action potential amplitude (APA) and action potential duration at 50% repolarization (APD50) decreased with temperature increases, and APD50 was more thermally sensitive than APA. EP and tissue changes were irreversible when HIFU-induced temperature increased above 52.3 ± 1.4°C and log10(CEM43) above 2.16 ± 0.51 (n = 5), but were reversible when temperature was below 50.1 ± 0.8°C and log10(CEM43) below -0.9 ± 0.3 (n = 9). EP and temperature/thermal dose changes were spatially correlated with HIFU-induced tissue necrosis surrounded by a transition zone. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.
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Osadchii, Oleg E
2014-12-01
In the clinical setting, patients with slower resting heart rate are less prone to cardiovascular death compared with those with elevated heart rate. However, electrophysiological adaptations associated with reduced cardiac rhythm have not been thoroughly explored. In this study, relationships between intrinsic heart rate and arrhythmic susceptibility were examined by assessments of action potential duration (APD) rate adaptation and inducibility of repolarization alternans in sinoatrial node (SAN)-driven and atrioventricular (AV)-blocked guinea-pig hearts perfused with Langendorff apparatus. Electrocardiograms, epicardial monophasic action potentials, and effective refractory periods (ERP) were assessed in normokalemic and hypokalemic conditions. Slower basal heart rate in AV-blocked hearts was associated with prolonged ventricular repolarization during spontaneous beating, and with attenuated APD shortening at increased cardiac activation rates during dynamic pacing, when compared with SAN-driven hearts. During hypokalemic perfusion, the inducibility of repolarization alternans and tachyarrhythmia by rapid pacing was found to be lower in AV-blocked hearts. This difference was ascribed to prolonged ERP in the setting of reduced basal heart rate, which prevented ventricular capture at critically short pacing intervals required to induce arrhythmia. Reduced basal heart rate is associated with electrophysiological changes that prevent electrical instability upon an abrupt cardiac acceleration.
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Frequency-dependence of the slow force response.
von Lewinski, Dirk; Zhu, Danan; Khafaga, Mounir; Kockskamper, Jens; Maier, Lars S; Hasenfuss, Gerd; Pieske, Burkert
2008-05-01
Stretch induces biphasic inotropic effects in mammalian myocardium. A delayed component (slow force response, SFR) has been demonstrated in various species, however, experimental conditions varied and the underlying mechanisms are controversial. The physiological relevance of the SFR is poorly understood. Experiments were performed in ventricular muscle strips from failing human hearts and non-failing rabbit hearts. Upon stretch, twitch force was assessed at basal conditions (1 Hz, 37 degrees C) and after changing stimulation frequency with and without blockade of the Na+/H+-exchanger-1 (NHE1) or reverse-mode Na+/Ca2+-exchange (NCX). Action potential duration (APD) was assessed using floating electrodes. Low stimulation rates (0.2 Hz) potentiated and higher stimulation rates (2 and 3 Hz) reduced the SFR. The extent of SFR inhibition by NHE1 or NCX inhibition was not affected by stimulation rate. APD decreased at 0.2 Hz but was not altered at higher stimulation rates. The data demonstrate frequency-dependence of the SFR with greater positive inotropic effects at lower stimulation rates. Subcellular mechanisms underlying the SFR are not fundamentally affected by stimulation rate. The SFR may have more pronounced physiological effects at lower heart rates.
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Wuriyanghai, Yimin; Makiyama, Takeru; Sasaki, Kenichi; Kamakura, Tsukasa; Yamamoto, Yuta; Hayano, Mamoru; Harita, Takeshi; Nishiuchi, Suguru; Chen, Jiarong; Kohjitani, Hirohiko; Hirose, Sayako; Yokoi, Fumika; Gao, Jingshan; Chonabayashi, Kazuhisa; Watanabe, Ken; Ohno, Seiko; Yoshida, Yoshinori; Kimura, Takeshi; Horie, Minoru
2018-05-29
Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1, which encodes the α-subunit of the slow delayed rectifier potassium current (I Ks ) channel. We previously reported that a synonymous mutation, c.1032G>A, p.A344Aspl in KCNQ1 is most commonly identified in the genotyped LQT1 Japanese patients, and the aberrant splicing was analyzed in the lymphocytes isolated from patients' blood samples. However, the mechanisms underlying the observed processes in human cardiomyocytes remains unclear. To establish and analyze patient-specific human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model carrying KCNQ1-A344Aspl. We generated hiPSCs from the peripheral blood mononuclear cells obtained from an LQT1 patient carrying KCNQ1-A344Aspl. Using the differentiated cardiomyocytes, we analyzed splicing variants and performed electrophysiological studies. We identified seven aberrant RNA variants in A344Aspl-hiPSC-CMs, more complex compared with those in the peripheral lymphocytes. Multi-electrode array analysis revealed that 1 μM isoproterenol significantly prolonged the duration of corrected field potential in A344Aspl-hiPSC-CMs, compared with that in the controls. Additionally, 100 nM E-4031, I Kr blocker, was shown to induce early afterdepolarization-like waveforms in A344Aspl-hiPSC-CMs. Action potential durations (APDs) did not significantly differ between the hiPSC-CM groups. After administrating 500 nM isoproterenol, APDs of A344Aspl-hiPSC-CMs were significantly longer than those of the controls. ML277 and phenylboronic acid, I Ks activators, ameliorated the APDs of hiPSC-CMs. We identified complex aberrant mRNA variants in the A344Aspl-hiPSC-CM model, and successfully recapitulated the clinical phenotypes of the patient with concealed LQT1. This model allows the investigation of the underlying mechanisms and development of novel therapies. Copyright © 2018. Published by Elsevier Inc.
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[Auditory processing and high frequency audiometry in students of São Paulo].
Ramos, Cristina Silveira; Pereira, Liliane Desgualdo
2005-01-01
Auditory processing and auditory sensibility to high Frequency sounds. To characterize the localization processes, temporal ordering, hearing patterns and detection of high frequency sounds, looking for possible relations between these factors. 32 hearing fourth grade students, born in city of São Paulo, were submitted to: a simplified evaluation of the auditory processing; duration pattern test; high frequency audiometry. Three (9,4%) individuals presented auditory processing disorder (APD) and in one of them there was the coexistence of lower hearing thresholds in high frequency audiometry. APD associated to an auditory sensibility loss in high frequencies should be further investigated.
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Anton, Marja E; Baskin-Sommers, Arielle R; Vitale, Jennifer E; Curtin, John J; Newman, Joseph P
2012-12-01
Psychopathy and antisocial personality disorder (APD) have long been considered important risk factors for criminal behavior and incarceration. However, little is known about the psychobiological underpinnings that give rise to the disinhibited behavior of female offenders. Using an instructed fear-conditioning paradigm and a sample of incarcerated female offenders, we manipulated attentional focus and cognitive load to characterize and differentiate between the dysfunctional cognitive and affective processes associated with these syndromes. We used fear-potentiated startle (FPS) and event-related potentials as measures of affective and cognitive processing, respectively. After controlling for APD symptoms, psychopathic women displayed greater FPS while attending directly to threat-relevant stimuli and displayed less FPS while performing a demanding task that directed attention to threat-irrelevant information. Conversely, controlling for psychopathy, women with high APD symptoms displayed less overall FPS, especially when instructed to focus on threat-relevant stimuli. However, as the demands on cognitive resources increased, they displayed greater FPS. For both psychopathy and APD, analysis of the event-related potentials qualified these findings and further specified the abnormal cognitive processes associated with these two syndromes. Overall, simultaneous analysis of psychopathy and APD revealed distinct patterns of cognitive processing and fear reactivity.
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Garrott, Kara; Kuzmiak‐Glancy, Sarah; Wengrowski, Anastasia; Zhang, Hanyu; Rogers, Jack
2017-01-01
Key points Heart function is critically dependent upon the balance of energy production and utilization. Sarcolemmal ATP‐sensitive potassium channels (KATP channels) in cardiac myocytes adjust contractile function to compensate for the level of available energy.Understanding the activation of KATP channels in working myocardium during high‐stress situations is crucial to the treatment of cardiovascular disease, especially ischaemic heart disease.Using a new optical mapping approach, we measured action potentials from the surface of excised contracting rabbit hearts to assess when sarcolemmal KATP channels were activated during physiologically relevant workloads and during gradual reductions in myocardial oxygenation.We demonstrate that left ventricular pressure is closely linked to KATP channel activation and that KATP channel inhibition with a low concentration of tolbutamide prevents electromechanical decline when oxygen availability is reduced. As a result, KATP channel inhibition probably exacerbates a mismatch between energy demand and energy production when myocardial oxygenation is low. Abstract Sarcolemmal ATP‐sensitive potassium channel (KATP channel) activation in isolated cells is generally understood, although the relationship between myocardial oxygenation and KATP activation in excised working rabbit hearts remains unknown. We optically mapped action potentials (APs) in excised rabbit hearts to test the hypothesis that hypoxic changes would be more severe in left ventricular (LV) working hearts (LWHs) than Langendorff (LANG) perfused hearts. We further hypothesized that KATP inhibition would prevent those changes. Optical APs were mapped when measuring LV developed pressure (LVDP), coronary flow rate and oxygen consumption in LANG and LWHs. Hearts were paced to increase workload and perfusate was deoxygenated to study the effects of myocardial hypoxia. A subset of hearts was perfused with 1 μm tolbutamide (TOLB) to identify the level of AP duration (APD) shortening attributed to KATP channel activation. During sinus rhythm, APD was shorter in LWHs compared to LANG hearts. APD in both LWHs and LANG hearts dropped steadily during deoxygenation. With TOLB, APDs in LWHs were longer at all workloads and APD reductions during deoxygenation were blunted in both LWHs and LANG hearts. At 50% perfusate oxygenation, APD and LVDP were significantly higher in LWHs perfused with TOLB (199 ± 16 ms; 92 ± 5.3 mmHg) than in LWHs without TOLB (109 ± 14 ms, P = 0.005; 65 ± 6.5 mmHg, P = 0.01). Our results indicate that KATP channels are activated to a greater extent in perfused hearts when the LV performs pressure–volume work. The results of the present study demonstrate the critical role of KATP channels in modulating myocardial function over a wide range of physiological conditions. PMID:28177123
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Benoist, David; Stones, Rachel; Benson, Alan P.; Fowler, Ewan D.; Drinkhill, Mark J.; Hardy, Matthew E.L.; Saint, David A.; Cazorla, Olivier; Bernus, Olivier; White, Ed
2014-01-01
We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats. We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate. Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations. PMID:25016242
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Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: Insights from virtual human atria
El Harchi, Aziza; Hancox, Jules C.
2017-01-01
Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on IK1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of IK1 and IKr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas IKr block alone may be a safer alternative for the E299V mutation. Combined inhibition of IKr and IKur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF. PMID:28609477
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Sánchez, Carlos; Corrias, Alberto; Bueno-Orovio, Alfonso; Davies, Mark; Swinton, Jonathan; Jacobson, Ingemar; Laguna, Pablo; Pueyo, Esther; Rodríguez, Blanca
2012-03-01
Pharmacological treatment of atrial fibrillation (AF) exhibits limited efficacy. Further developments require a comprehensive characterization of ionic modulators of electrophysiology in human atria. Our aim is to systematically investigate the relative importance of ionic properties in modulating excitability, refractoriness, and rotor dynamics in human atria before and after AF-related electrical remodeling (AFER). Computer simulations of single cell and tissue atrial electrophysiology were conducted using two human atrial action potential (AP) models. Changes in AP, refractory period (RP), conduction velocity (CV), and rotor dynamics caused by alterations in key properties of all atrial ionic currents were characterized before and after AFER. Results show that the investigated human atrial electrophysiological properties are primarily modulated by maximal value of Na(+)/K(+) pump current (G(NaK)) as well as conductances of inward rectifier potassium current (G(K1)) and fast inward sodium current (G(Na)). G(NaK) plays a fundamental role through both electrogenic and homeostatic modulation of AP duration (APD), APD restitution, RP, and reentrant dominant frequency (DF). G(K1) controls DF through modulation of AP, APD restitution, RP, and CV. G(Na) is key in determining DF through alteration of CV and RP, particularly in AFER. Changes in ionic currents have qualitatively similar effects in control and AFER, but effects are smaller in AFER. The systematic analysis conducted in this study unravels the important role of the Na(+)/K(+) pump current in determining human atrial electrophysiology.
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Xiong, Liang; Liu, Yu; Zhou, Mingmin; Wang, Guangji; Quan, Dajun; Shen, Caijie; Shuai, Wei; Kong, Bin; Huang, Congxin; Huang, He
2018-05-31
The purpose of this study was to evaluate the cardiac electrophysiologic effects of targeted ablation of cardiac sympathetic neurons (TACSN) in a canine model of chronic myocardial infarction (MI). Thirty-eight anaesthetized dogs were randomly assigned into the sham-operated, MI, and MI-TACSN groups, respectively. Myocardial infarction-targeted ablation of cardiac sympathetic neuron was induced by injecting cholera toxin B subunit-saporin compound in the left stellate ganglion (LSG). Five weeks after surgery, the cardiac function, heart rate variability (HRV), ventricular electrophysiological parameters, LSG function and neural activity, serum norepinephrine (NE), nerve growth factor (NGF), and brain natriuretic peptide (BNP) levels were measured. Cardiac sympathetic innervation was determined with immunofluorescence staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Compared with MI group, TACSN significantly improved HRV, attenuated LSG function and activity, prolonged corrected QT interval, decreased Tpeak-Tend interval, prolonged ventricular effective refractory period (ERP), and action potential duration (APD), decreased the slopes of APD restitution curves, suppressed the APD alternans, increased ventricular fibrillation threshold, and reduced serum NE, NGF, and BNP levels. Moreover, the densities of GAP43 and TH-positive nerve fibres in the infarcted border zone in the MI-TACSN group were lower than those in the MI group. Targeted ablation of cardiac sympathetic neuron attenuates sympathetic remodelling and improves ventricular electrical remodelling in the chronic phase of MI. These data suggest that TACSN may be a novel approach to treating ventricular arrhythmias.
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Anton, Marja E.; Vitale, Jennifer E.; Curtin, John J.; Newman, Joseph P.
2012-01-01
Psychopathy and antisocial personality disorder (APD) have long been considered important risk factors for criminal behavior and incarceration. However, little is known about the psychobiological underpinnings that give rise to the disinhibited behavior of female offenders. Using an instructed fear-conditioning paradigm and a sample of incarcerated female offenders, we manipulated attentional focus and cognitive load to characterize and differentiate between the dysfunctional cognitive and affective processes associated with these syndromes. We used fear-potentiated startle (FPS) and event-related potentials as measures of affective and cognitive processing, respectively. After controlling for APD symptoms, psychopathic women displayed greater FPS while attending directly to threat-relevant stimuli and displayed less FPS while performing a demanding task that directed attention to threat-irrelevant information. Conversely, controlling for psychopathy, women with high APD symptoms displayed less overall FPS, especially when instructed to focus on threat-relevant stimuli. However, as the demands on cognitive resources increased, they displayed greater FPS. For both psychopathy and APD, analysis of the event-related potentials qualified these findings and further specified the abnormal cognitive processes associated with these two syndromes. Overall, simultaneous analysis of psychopathy and APD revealed distinct patterns of cognitive processing and fear reactivity. PMID:22886692
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Janelidze, Shorena; Hall, Sara; Magdalinou, Nadia; Lees, Andrew J.; Andreasson, Ulf; Norgren, Niklas; Linder, Jan; Forsgren, Lars; Constantinescu, Radu; Zetterberg, Henrik; Blennow, Kaj
2017-01-01
Objective: To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders. Methods: The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated. Results: We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73–0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81). Conclusions: Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics. Classification of evidence: This study provides Class III evidence that blood NfL levels discriminate between PD and APD. PMID:28179466
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Bellis, Teri James; Billiet, Cassie; Ross, Jody
2011-09-01
Cacace and McFarland (2005) have suggested that the addition of cross-modal analogs will improve the diagnostic specificity of (C)APD (central auditory processing disorder) by ensuring that deficits observed are due to the auditory nature of the stimulus and not to supra-modal or other confounds. Others (e.g., Musiek et al, 2005) have expressed concern about the use of such analogs in diagnosing (C)APD given the uncertainty as to the degree to which cross-modal measures truly are analogous and emphasize the nonmodularity of the CANs (central auditory nervous system) and its function, which precludes modality specificity of (C)APD. To date, no studies have examined the clinical utility of cross-modal (e.g., visual) analogs of central auditory tests in the differential diagnosis of (C)APD. This study investigated performance of children diagnosed with (C)APD, children diagnosed with ADHD (attention deficit hyperactivity disorder), and typically developing children on three diagnostic tests of central auditory function and their corresponding visual analogs. The study sought to determine whether deficits observed in the (C)APD group were restricted to the auditory modality and the degree to which the addition of visual analogs aids in the ability to differentiate among groups. An experimental repeated measures design was employed. Participants consisted of three groups of right-handed children (normal control, n=10; ADHD, n=10; (C)APD, n=7) with normal and symmetrical hearing sensitivity, normal or corrected-to-normal visual acuity, and no family or personal history of disorders unrelated to their primary diagnosis. Participants in Groups 2 and 3 met current diagnostic criteria for ADHD and (C)APD. Visual analogs of three tests in common clinical use for the diagnosis of (C)APD were used (Dichotic Digits [Musiek, 1983]; Frequency Patterns [Pinheiro and Ptacek, 1971]; and Duration Patterns [Pinheiro and Musiek, 1985]). Participants underwent two 1 hr test sessions separated by at least 1 wk. Order of sessions (auditory, visual) and tests within each session were counterbalanced across participants. ANCOVAs (analyses of covariance) were used to examine effects of group, modality, and laterality (Dichotic/Dichoptic Digits) or response condition (auditory and visual patterning). In addition, planned univariate ANCOVAs were used to examine effects of group on intratest comparison measures (REA, HLD [Humming-Labeling Differential]). Children with both ADHD and (C)APD performed more poorly overall than typically developing children on all tasks, with the (C)APD group exhibiting the poorest performance on the auditory and visual patterns tests but the ADHD and (C)APD group performing similarly on the Dichotic/Dichoptic Digits task. However, each of the auditory and visual intratest comparison measures, when taken individually, was able to distinguish the (C)APD group from both the normal control and ADHD groups, whose performance did not differ from one another. Results underscore the importance of intratest comparison measures in the interpretation of central auditory tests (American Speech-Language-Hearing Association [ASHA], 2005 ; American Academy of Audiology [AAA], 2010). Results also support the "non-modular" view of (C)APD in which cross-modal deficits would be predicted based on shared neuroanatomical substrates. Finally, this study demonstrates that auditory tests alone are sufficient to distinguish (C)APD from supra-modal disorders, with cross-modal analogs adding little if anything to the differential diagnostic process. American Academy of Audiology.
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Shaheen, Naim; Shiti, Assad; Huber, Irit; Shinnawi, Rami; Arbel, Gil; Gepstein, Amira; Setter, Noga; Goldfracht, Idit; Gruber, Amit; Chorna, Snizhanna V; Gepstein, Lior
2018-06-05
Fulfilling the potential of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes for studying conduction and arrhythmogenesis requires development of multicellular models and methods for long-term repeated tissue phenotyping. We generated confluent hiPSC-derived cardiac cell sheets (hiPSC-CCSs), expressing the genetically encoded voltage indicator ArcLight. ArcLight-based optical mapping allowed generation of activation and action-potential duration (APD) maps, which were validated by mapping the same hiPSC-CCSs with the voltage-sensitive dye, Di-4-ANBDQBS. ArcLight mapping allowed long-term assessment of electrical remodeling in the hiPSC-CCSs and evaluation of drug-induced conduction slowing (carbenoxolone, lidocaine, and quinidine) and APD prolongation (quinidine and dofetilide). The latter studies also enabled step-by-step depiction of drug-induced arrhythmogenesis ("torsades de pointes in the culture dish") and its prevention by MgSO 4 and rapid pacing. Phase-mapping analysis allowed biophysical characterization of spiral waves induced in the hiPSC-CCSs and their termination by electrical cardioversion and overdrive pacing. In conclusion, ArcLight mapping of hiPSC-CCSs provides a powerful tool for drug testing and arrhythmia investigation. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Adherence of pediatric patients to automated peritoneal dialysis.
Chua, Annabelle N; Warady, Bradley A
2011-05-01
Little information is available on adherence to a home automated peritoneal dialysis (APD) prescription for children with end-stage renal disease. We have therefore retrospectively reviewed HomeChoice PRO Card data from patients <21 years of age who received home APD. Adherence was characterized as occurring ≥ 95%, 90-94%, or <90% of time by dividing the frequency of each of four measured prescription variables (sessions/month, duration of each session, number of cycles/session, volume of dialysate/session) by the prescribed frequency and multiplying by 100. The relationship between treatment adherence and patient age, gender, race and if the patient had received training, respectively, was assessed. Of the 51 patients (57% male), with a mean age at peritoneal dialysis (PD) onset of 11.8 ± 5.3 years, 28 (55%) were adherent for all variables. No difference in mean age or if patients were trained existed between the two groups. Males were more likely to be non-adherent (p = 0.026) as were African Americans (p = 0.048). The majority of patients were adherent to duration (96%) and number of cycles (92%), whereas non-adherence was more common with number of sessions (82%) and dialysate volume (78%). In conclusion, 45% of the pediatric patients in our study cohort exhibited some non-adherence to their prescribed APD regimen, emphasizing the value of closely monitoring the performance of home dialysis in children.
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In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk.
Romero, Lucia; Cano, Jordi; Gomis-Tena, Julio; Trenor, Beatriz; Sanz, Ferran; Pastor, Manuel; Saiz, Javier
2018-04-23
Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue. Multiple channel-drug interactions and state-of-the-art human ventricular action potential models ( O'Hara , T. , PLos Comput. Biol. 2011 , 7 , e1002061 ) were used in our simulations. Specifically, 206.766 cellular and 7072 tissue simulations were performed by blocking the slow and the fast components of the delayed rectifier current ( I Ks and I Kr , respectively) and the L-type calcium current ( I CaL ) at different levels. The performance of our system was validated by classifying the proarrhythmic risk of 84 compounds, 40 of which present torsadogenic properties. On the basis of these results, we propose the use of a new index (Tx) for discriminating torsadogenic compounds, defined as the ratio of the drug concentrations producing 10% prolongation of the cellular endocardial, midmyocardial, and epicardial APDs and the QT interval, over the maximum effective free therapeutic plasma concentration (EFTPC). Our results show that the Tx index outperforms standard methods for early identification of torsadogenic compounds. Indeed, for the analyzed compounds, the Tx tests accuracy was in the range of 87-88% compared with a 73% accuracy of the hERG IC 50 based test.
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Jehle, J; Ficker, E; Wan, X; Deschenes, I; Kisselbach, J; Wiedmann, F; Staudacher, I; Schmidt, C; Schweizer, PA; Becker, R; Katus, HA; Thomas, D
2013-01-01
Background and Purpose Zolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene (hERG)/IKr currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K+ channels. Experimental Approach Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration (APD) was assessed in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. Key Results Zolpidem caused acute hERG channel blockade in oocytes (IC50 = 61.5 μM) and in HEK 293 cells (IC50 = 65.5 μM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage- and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I–V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes. Conclusions and Implications Zolpidem inhibits cardiac hERG K+ channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose. PMID:23061993
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Wang, Jin-Cheng; Kiyosue, Tatsuto; Kiriyama, Kuninori; Arita, Makoto
1999-01-01
We investigated the effects of bepridil on the two components of the delayed rectifier K+ current, i.e., the rapidly activating (IKr) and the slowly activating (IKs) currents using tight-seal whole-cell patch-clamp techniques in guinea-pig ventricular myocytes, under blockade of L-type Ca2+ current with nitrendipine (5 μM) or D600 (1 μM).Bepridil decreased IKs under blockade of IKr with E4031 (5 μM), in a concentration-dependent manner. The concentration-dependent inhibition of IKs by bepridil was fitted by a curve, assuming one-to-one interactions between the channel and the drug molecule. The concentration of half-maximal inhibition (IC50) was found to be 6.2 μM.The effect of bepridil on IKr was assessed using an envelope-of-tails test. In the control condition, a ratio of the tail current to the time-dependent current measured during depolarization was large (>1) at shorter pulses (<200 ms), and it decreased to a steady state value of ∼0.4 with increases in the pulse duration. Bepridil at a concentration of 2 μM did not decrease this ratio at shorter pulses.In a short-pulse (duration=50 ms) experiment that largely activates IKr, the drug was found to block IKr in a cooperative manner (Hill coefficient=3.03) and the IC50 was 13.2 μM.These results suggest that bepridil at a clinical therapeutic concentration (∼2 μM) selectively blocks IKs but does not inhibit IKr. This may relate to the characteristic frequency-dependent effects of bepridil on the action potential duration (APD), e.g., the non-reverse use-dependent prolongation of APD. PMID:10588929
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Steinberg, M.I.; Wiest, S.A.; Zimmerman, K.M.
1991-01-01
Pinacidil, a potassium channel opener (PCO), relaxes vascular smooth muscle by increasing potassium ion membrane conductance, thereby causing membrane hyperpolarization. PCOs also act on cardiac muscle to decrease action potential duration (APD) selectively. To examine the enantiomeric selectivity of pinacidil, the stereoisomers of pinacidil (a 4-pyridylcyanoguanidine) and its 3-pyridyl isomer (LY222675) were synthesized and studied in canine Purkinje fibers and cephalic veins. The (-)-enantiomers of both pinacidil and LY222675 were more potent in relaxing phenylephrine-contracted cephalic veins and decreasing APD than were their corresponding (+)-enantiomers. The EC50 values for (-)-pinacidil and (-)-LY222675 in relaxing cephalic veins were 0.44 and 0.09more » microM, respectively. In decreasing APD, the EC50 values were 3.2 microM for (-)-pinacidil and 0.43 microM for (-)-LY222675. The eudismic ratio was greater for the 3-pyridyl isomer than for pinacidil in both cardiac (71 vs. 22) and vascular (53 vs. 17) tissues. (-)-LY222675 and (-)-pinacidil (0.1-30 microM) also increased 86Rb efflux from cephalic veins to a greater extent than did their respective optical antipodes. The antidiabetic sulfonylurea, glyburide (1-30 microM), shifted the vascular concentration-response curve of (-)-pinacidil to the right by a similar extent at each inhibitor concentration. Glipizide also antagonized the response to (-)-pinacidil, but was about 1/10 as potent with a maximal shift occurring at 10 and 30 microM. Glyburide antagonized the vascular relaxant effects of 0.3 microM (-)-LY222675 (EC50, 2.3 microM) and reversed the decrease in APD caused by 3 microM (-)-LY222675 (EC50, 1.9 microM). Nitroprusside did not alter 86Rb efflux, and vascular relaxation induced by sodium nitroprusside was unaffected by sulfonylureas.« less
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Rate dependency of delayed rectifier currents during the guinea-pig ventricular action potential
Rocchetti, Marcella; Besana, Alessandra; Gurrola, Georgina B; Possani, Lourival D; Zaza, Antonio
2001-01-01
The action potential clamp technique was exploited to evaluate the rate dependency of delayed rectifier currents (IKr and IKs) during physiological electrical activity. IKr and IKs were measured in guinea-pig ventricular myocytes at pacing cycle lengths (CL) of 1000 and 250 ms.A shorter CL, with the attendant changes in action potential shape, was associated with earlier activation and increased magnitude of both IKr and IKs. Nonetheless, the relative contributions of IKr and IKs to total transmembrane current were independent of CL.Shortening of diastolic interval only (constant action potential shape) enhanced IKs, but not IKr.IKr was increased by a change in the action potential shape only (constant diastolic interval).In ramp clamp experiments, IKr amplitude was directly proportional to repolarization rate at values within the low physiological range (< 1.0 V s−1); at higher repolarization rates proportionality became shallower and finally reversed.When action potential duration (APD) was modulated by constant current injection (I-clamp), repolarization rates > 1.0 V s−1 were associated with a reduced effect of IKr block on APD. The effect of changes in repolarization rate was independent of CL and occurred in the presence of IKs blockade.In spite of its complexity, the behaviour of IKr was accurately predicted by a numerical model based entirely on known kinetic properties of the current.Both IKr and IKs may be increased at fast heart rates, but this may occur through completely different mechanisms. The mechanisms identified are such as to contribute to abnormal rate dependency of repolarization in prolonged repolarization syndromes. PMID:11483703
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Abramochkin, Denis V; Vornanen, Matti
2015-12-01
Several freshwater fishes of north-temperate latitudes exhibit marked seasonal changes in cardiac action potential (AP) waveform as an outcome of temperature-dependent changes in the density of delayed rectifiers (IKr, IKs) and inward rectifier (IK1) potassium currents. Thus far, ionic mechanisms of cardiac excitability in arctic marine fishes have not been examined. To this end we examined ventricular AP and the role of two major potassium currents (IK1, IKr) in repolarization of cardiac AP in winter-acclimatized (WA, caught in March) and summer-acclimatized (SA, caught in September) navaga cod (Eleginus navaga) of the White Sea. The duration of ventricular AP of WA navaga at 3 °C (APD50 = 659.5 ± 32.8 ms) was similar to the AP duration of SA navaga at 12 °C (APD50 = 543.9 ± 14.6 ms) (p > 0.05) indicating complete thermal compensation of AP duration. This acclimation effect was associated with strong up-regulation of the cardiac potassium currents in winter. Densities of ventricular IK1 (at -120 mV) and IKr (at +50 mV) of the WA navaga at 3 °C were 2.9 times and 2.8 times, respectively, higher than those of the SA navaga at 12 °C, thus indicating marked thermal overcompensation. Qualitatively similar results were obtained from atrial myocytes. Seasonal changes in IK1 and IKr are more than sufficient to explain the complete thermal compensation of ventricular AP duration. The excellent acclimation capacity of cardiac excitability of the navaga cod is probably needed to maintain high cardiac performance at subzero temperatures in winter and to increase thermal resilience of cardiac function under seasonally variable arctic temperature conditions.
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Pousset, M; Tremblay, R E; Falissard, B
2011-06-01
The aim of this study was to contribute to clarification of the relations between antisocial personality disorder (APD) and its potential risk factors in a population of 560 French male prisoners. Adverse childhood was assessed as a latent variable determined by several traumatic events. APD (MINI), character and temperament (Cloninger's model), WAIS®-III similarities subtest and psychosocial characteristics were assessed by two clinicians. The WAIS®-III subtest accounts for verbal and cognitive performance. We used a structural model to determine the weight of the different pathways between adverse childhood and APD. Study confirmed the major and direct role of adverse childhood (standardized coefficient=0.48). An intermediate effect mediated by character (considered as a global variable) and novelty-seeking was also shown, confirming previous results from the literature. This study emphasizes the role of adverse childhood in APD, suggesting the potential benefit of early intervention in the prevention of antisocial behaviours. Copyright © 2011. Published by Elsevier Masson SAS.
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2012-01-01
A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels. PMID:24900457
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Huang, Bing; Zhou, Xiaoya; Wang, Menglong; Li, Xuefei; Zhou, Liping; Meng, Guannan; Wang, Yuhong; Wang, Zhuo; Wang, Songyun; Yu, Lilei; Jiang, Hong
2018-06-01
Blood pressure elevation in response to transient renal nerve stimulation (RNS) has been used to determine the ablation target and endpoint of renal denervation. This study aimed to evaluate the safety of transient RNS in canines with normal or ischaemic hearts. In ten normal (Group 1) and six healed myocardial infarction (HMI) (Group 2) canines, a large-tip catheter was inserted into the left or right renal artery to perform transient RNS. The left stellate ganglion neural activity (LSGNA) and ventricular electrophysiological parameters were measured at baseline and during transient RNS. In another 20 acute myocardial infarction (AMI) canines, RNS (Group 3, n = 10) or sham RNS (Group 4, n = 10) was intermittently (1 min ON and 4 min OFF) performed for 1 h following AMI induction. The LSGNA and AMI-induced ventricular arrhythmias were analysed. In normal and HMI canines, although transient RNS significantly increased the LSGNA and facilitated the action potential duration (APD) alternans, it did not induce any ventricular arrhythmias and did not change the ventricular effective refractory period, APD or maximum slope of the APD restitution curve. In AMI canines, transient RNS significantly exacerbated LSG activation and promoted the incidence of ventricular arrhythmias. Transient RNS did not increase the risk of ventricular arrhythmias in normal or HMI hearts, but it significantly promoted the occurrence of ventricular arrhythmias in AMI hearts. Therefore, electrical stimulation-based renal nerve mapping may be unsafe in AMI patients and in patients with a high risk for malignant ventricular arrhythmias.
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Effects of sildenafil on cardiac repolarization.
Chiang, Chern-En; Luk, Hsiang-Ning; Wang, Tsui-Min; Ding, Philip Yu-An
2002-08-01
Sudden death has occasionally been reported in patients taking sildenafil. The objective of this study was to investigate the effect of sildenafil on cardiac repolarization. We used conventional microelectrode recording technique in isolated guinea pig papillary muscles and canine Purkinje fibers, whole-cell patch clamp techniques in guinea pig ventricular myocytes, and in vivo ECG measurements in guinea pigs. Action potential duration at 90% repolarization (APD(90)) was not affected by sildenafil in the therapeutic ranges (< or =1 microM), but shortened by higher concentration (> or =10 microM) in both guinea pig papillary muscles and canine Purkinje fibers. D-Sotalol prolonged APD(90) in the same preparations with concentrations > or =1 microM in a reverse frequency-dependent manner. Co-administration of sildenafil (10 and 30 microM) abolished the APD-prolonging effects of D-sotalol (30 microM) and amiodarone (100 microM). Sildenafil, with concentrations up to 30 microM, had no significant effect on both the rapid (I(Kr)) and the slow (I(Ks)) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes. Sildenafil dose-dependently blocked L-type Ca(2+) current (I(Ca,L)), but had no effect on persistent Na(+) current in guinea pig ventricular myocytes. ECG recordings in intact guinea pigs revealed significant shortening of QTc interval by sildenafil (10 and 30 mg/kg orally). The QT-prolonging effects by D,L-sotalol (50 mg/kg) and amiodarone (100 mg/kg) were abolished by sildenafil (30 mg/kg). Sildenafil does not prolong cardiac repolarization. Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably through its blocking effect on I(Ca,L).
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Bradycardia alters Ca2+ dynamics enhancing dispersion of repolarization and arrhythmia risk
Kim, Jong J.; Němec, Jan; Papp, Rita; Strongin, Robert; Abramson, Jonathan J.
2013-01-01
Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca2+ transients and APs were measured optically from Langendorff rabbit hearts at high (150 × 150 μm2) or low (1.5 × 1.5 cm2) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR = 50 beats/min). Western blots and pharmacological interventions were used to elucidate the regional effects of bradycardia. As a result, bradycardia (SHR 50 beats/min) increased APDs gradually (time constant τf→s = 48 ± 9.2 s) and caused a secondary Ca2+ release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 ± 9.7 ms after the Ca2+ transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca2+ release events leading to subcellular Ca2+ waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation (P < 0.01, n = 5), enhanced DOR (r = 0.9277 ± 0.03, n = 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening (P < 0.05, n = 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)propan-1-one (K201; 1 μM), suppressed SCR and reduced APD at the base, thereby reducing DOR (P < 0.02, n = 5). Ventricular ectopy induced by bradycardia (n = 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca2+ channel protein (Cav1.2α), Na+-Ca2+ exchange (NCX1), voltage-gated Na+ channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca2+ ATPase 2a] that correlate with the SCR distribution and explain the molecular basis for SCR heterogeneities. In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations. PMID:23316064
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A mathematical model of action potential heterogeneity in adult rat left ventricular myocytes.
Pandit, S V; Clark, R B; Giles, W R; Demir, S S
2001-01-01
Mathematical models were developed to reconstruct the action potentials (AP) recorded in epicardial and endocardial myocytes isolated from the adult rat left ventricle. The main goal was to obtain additional insight into the ionic mechanisms responsible for the transmural AP heterogeneity. The simulation results support the hypothesis that the smaller density and the slower reactivation kinetics of the Ca(2+)-independent transient outward K(+) current (I(t)) in the endocardial myocytes can account for the longer action potential duration (APD), and more prominent rate dependence in that cell type. The larger density of the Na(+) current (I(Na)) in the endocardial myocytes results in a faster upstroke (dV/dt(max)). This, in addition to the smaller magnitude of I(t), is responsible for the larger peak overshoot of the simulated endocardial AP. The prolonged APD in the endocardial cell also leads to an enhanced amplitude of the sustained K(+) current (I(ss)), and a larger influx of Ca(2+) ions via the L-type Ca(2+) current (I(CaL)). The latter results in an increased sarcoplasmic reticulum (SR) load, which is mainly responsible for the higher peak systolic value of the Ca(2+) transient [Ca(2+)](i), and the resultant increase in the Na(+)-Ca(2+) exchanger (I(NaCa)) activity, associated with the simulated endocardial AP. In combination, these calculations provide novel, quantitative insights into the repolarization process and its naturally occurring transmural variations in the rat left ventricle. PMID:11720973
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He, Jionghong; Xu, Yanan; Yang, Long; Xia, Guiling; Deng, Na; Yang, Yongyao; Tian, Ye; Fu, Zenan; Huang, Yongqi
2018-05-02
Previous studies have shown that the activation of angiotensin II receptor type I (AT 1 ) is attributed to cardiac remodeling stimulated by increased heart load, and that it is followed by the activation of the calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway. Additionally, AT 1 has been found to be a regulator of cardiocyte ionic channel remodeling, and calcineurin-NFAT signals participate in the regulation of cardiocyte ionic channel expression. A hypothesis therefore follows that stretch stimulation may regulate cardiocyte ionic channel remodeling by activating the AT 1 -calcineurin-NFAT pathway. Here, we investigated the role of the AT 1 -calcineurin-NFAT pathway in the remodeling of inward rectifier potassium (I k1 ) channel, in addition to its role in changing action potential, in stretch-induced hypertrophic atrial myocytes of neonatal rats. Our results showed that increased stretch significantly led to atrial myocytes hypertrophy; it also increased the activity of calcineurin enzymatic activity, which was subsequently attenuated by telmisartan or cyclosporine-A. The level of NFAT 3 protein in nuclear extracts, the mRNA and protein expression of Kir2.1 in whole cell extracts, and the density of I k1 were noticeably increased in stretched samples. Stretch stimulation significantly shortened the action potential duration (APD) of repolarization at the 50% and 90% level. Telmisartan, cyclosporine-A, and 11R-VIVIT attenuated stretch-induced alterations in the levels of NFAT 3 , mRNA and protein expression of Kir2.1, the density of I k1 , and the APD. Our findings suggest that the AT 1 -calcineurin-NFAT signaling pathway played an important role in regulating I k1 channel remodeling and APD change in stretch-induced hypertrophic atrial myocytes of neonatal rats. This article is protected by copyright. All rights reserved.
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Tucker, Kristal R; Block, Ethan R; Levitan, Edwin S
2015-08-11
Based on lysotracker red imaging in cultured hippocampal neurons, antipsychotic drugs (APDs) were proposed to accumulate in synaptic vesicles by acidic trapping and to be released in response to action potentials. Because many APDs are dopamine (DA) D2 receptor (D2R) antagonists, such a mechanism would be particularly interesting if it operated in midbrain DA neurons. Here, the APD cyamemazine (CYAM) is visualized directly by two-photon microscopy in substantia nigra and striatum brain slices. CYAM accumulated slowly into puncta based on vacuolar H(+)-ATPase activity and dispersed rapidly upon dissipating organelle pH gradients. Thus, CYAM is subject to acidic trapping and released upon deprotonation. In the striatum, Ca(2+)-dependent reduction of the CYAM punctate signal was induced by depolarization or action potentials. Striatal CYAM overlapped with the dopamine transporter (DAT). Furthermore, parachloroamphetamine (pCA), acting via vesicular monoamine transporter (VMAT), and a charged VMAT, substrate 1-methyl-4-phenylpyridinium (MPP(+)), reduced striatal CYAM. In vivo CYAM administration and in vitro experiments confirmed that clinically relevant CYAM concentrations result in vesicular accumulation and pCA-dependent release. These results show that some CYAM is in DA neuron VMAT vesicles and suggests a new drug interaction in which amphetamine induces CYAM deprotonation and release as a consequence of the H(+) countertransport by VMAT that accompanies vesicular uptake, but not by inducing exchange or acting as a weak base. Therefore, in the striatum, APDs are released with DA in response to action potentials and an amphetamine. This synaptic corelease is expected to enhance APD antagonism of D2Rs where and when dopaminergic transmission occurs.
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Use of antiparkinson medications among elderly Medicare beneficiaries with Parkinson's disease.
Wei, Yu-Jung Jenny; Stuart, Bruce; Zuckerman, Ilene H
2010-08-01
Antiparkinson drugs (APDs) are the mainstay in the management of Parkinson's disease (PD). However, the use of APDs has not been investigated in a nationally representative sample. This study aimed to describe the prevalence and patterns of APD use and to identify determinants of APD use among elderly Medicare beneficiaries with PD. Data from the Medicare Current Beneficiary Survey and Medicare claims from 2000 to 2003 were used to identify beneficiaries ≥65 years of age with PD. The APDs included in the study were levodopa, dopamine agonists, monoamine oxidase-B inhibitors, amantadine, anticholinergic agents, and catechol-O-methyltransferase inhibitors. The annual prevalence of APD use was calculated; patterns of APD use were measured by drug class and type of drug regimens (monotherapy or combination therapy). Potential determinants of APD use included sociodemographic characteristics (age, sex, race, education, marital status, and annual income), self-reported health status, residential status (institution or community), prescription drug coverage, disability (functional, physical, and mental), and disease-specific factors (dementia, depression, and other comorbidities). Multivariate logistic regression analyses with generalized estimating equations were used to estimate odds ratios (ORs) of any APD use associated with the determinants. The data revealed 571 beneficiaries with PD (30.1% aged ≥85 years, 55.0% female, 88.3% white), who were observed for a total of 924 person-years. The annual prevalence of APD use was 58.2% (538/924). Levodopa was the most frequently used agent, either as monotherapy or in combination with other APDs (85.5%; 460/538). Multivariate analyses found that patients 65 to 74 years of age (OR = 0.70; 95% CI, 0.49-0.99; P < 0.05) and those ≥85 years of age (OR = 0.57; 95% CI, 0.40-0.81; P < 0.01) were less likely to use APDs than were patients aged 75 to 84 years of age. Patients who had attained a high level of education (more than a high school diploma) were more likely to use APDs than were patients with a low level of education (a high school diploma or less) (OR = 1.51; 95% CI, 1.04-2.19; P < 0.05). In addition, institutionalization (OR = 1.78; 95% CI, 1.17-2.71; P < 0.01), prescription drug coverage (OR = 1.50; 95% CI, 1.15-1.94; P < 0.01), activities of daily living (ADLs) (OR = 1.47; 95% CI, 1.16-1.87; P < 0.01), and depression (OR = 1.25; 95% CI, 1.02-1.53; P < 0.05) were significantly associated with use of APDs. The probability of APD use was lower among those with dementia than among those without dementia (OR = 0.62; 95% CI, 0.48-0.80; P < 0.001). Almost half of the elderly Medicare beneficiaries with PD in this study did not use any APD between 2000 and 2003. Levodopa was the most frequently used APD, either as monotherapy or in combination with other APDs. The identified determinants of APD use (age, education, prescription drug coverage, ADLs, dementia, depression, and residing in an institution) may be helpful in developing interventions for this population. Copyright © 2010 Excerpta Medica Inc. All rights reserved.
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Shiloh, Roni; Valevski, Avi; Bodinger, Liron; Misgav, Sagit; Aizenberg, Dov; Dorfman-Etrog, Pnina; Weizman, Abraham; Munitz, Hanan
2003-05-01
Neuroleptic malignant syndrome (NMS) is a potentially lethal antipsychotic drug (APD)-induced thermoregulatory disturbance. We hypothesized that several precautionary measures taken after administeration of APDs might prevent progression to definite NMS. The study group included 657 consecutively admitted drug-free schizophrenia inpatients who received various typical APDs for 28 days. Specific predefined precautionary measures were employed for this group. The comparison group (n=192) consisted of typical APD-treated schizophrenia inpatients in whom such precautionary measures were not imposed. The study group exhibited a significantly lower incidence of definite NMS (1/657=0.2% versus 4/192=2.1%; P=0.01, odds ratio=13.96; 95% confidence interval 1.55-125.63). Antipsychotics were discontinued in 28 patients (28/657=4.3%) from the study group due to NMS (n=1) or early detection of potential NMS-related signs (probable abortive NMS) (n=27). Our findings suggest that specific precautionary measures can effectively reduce the incidence of definite NMS by approximately one order in newly medicated schizophrenia inpatients.
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Geiger-mode APD camera system for single-photon 3D LADAR imaging
NASA Astrophysics Data System (ADS)
Entwistle, Mark; Itzler, Mark A.; Chen, Jim; Owens, Mark; Patel, Ketan; Jiang, Xudong; Slomkowski, Krystyna; Rangwala, Sabbir
2012-06-01
The unparalleled sensitivity of 3D LADAR imaging sensors based on single photon detection provides substantial benefits for imaging at long stand-off distances and minimizing laser pulse energy requirements. To obtain 3D LADAR images with single photon sensitivity, we have demonstrated focal plane arrays (FPAs) based on InGaAsP Geiger-mode avalanche photodiodes (GmAPDs) optimized for use at either 1.06 μm or 1.55 μm. These state-of-the-art FPAs exhibit excellent pixel-level performance and the capability for 100% pixel yield on a 32 x 32 format. To realize the full potential of these FPAs, we have recently developed an integrated camera system providing turnkey operation based on FPGA control. This system implementation enables the extremely high frame-rate capability of the GmAPD FPA, and frame rates in excess of 250 kHz (for 0.4 μs range gates) can be accommodated using an industry-standard CameraLink interface in full configuration. Real-time data streaming for continuous acquisition of 2 μs range gate point cloud data with 13-bit time-stamp resolution at 186 kHz frame rates has been established using multiple solid-state storage drives. Range gate durations spanning 4 ns to 10 μs provide broad operational flexibility. The camera also provides real-time signal processing in the form of multi-frame gray-scale contrast images and single-frame time-stamp histograms, and automated bias control has been implemented to maintain a constant photon detection efficiency in the presence of ambient temperature changes. A comprehensive graphical user interface has been developed to provide complete camera control using a simple serial command set, and this command set supports highly flexible end-user customization.
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Remodeling of atrial ATP-sensitive K+ channels in a model of salt-induced elevated blood pressure
Lader, Joshua M.; Vasquez, Carolina; Bao, Li; Maass, Karen; Qu, Jiaxiang; Kefalogianni, Eirini; Fishman, Glenn I.; Coetzee, William A.
2011-01-01
Hypertension is associated with the development of atrial fibrillation; however, the electrophysiological consequences of this condition remain poorly understood. ATP-sensitive K+ (KATP) channels, which contribute to ventricular arrhythmias, are also expressed in the atria. We hypothesized that salt-induced elevated blood pressure (BP) leads to atrial KATP channel activation and increased arrhythmia inducibility. Elevated BP was induced in mice with a high-salt diet (HS) for 4 wk. High-resolution optical mapping was used to measure atrial arrhythmia inducibility, effective refractory period (ERP), and action potential duration at 90% repolarization (APD90). Excised patch clamping was performed to quantify KATP channel properties and density. KATP channel protein expression was also evaluated. Atrial arrhythmia inducibility was 22% higher in HS hearts compared with control hearts. ERP and APD90 were significantly shorter in the right atrial appendage and left atrial appendage of HS hearts compared with control hearts. Perfusion with 1 μM glibenclamide or 300 μM tolbutamide significantly decreased arrhythmia inducibility and prolonged APD90 in HS hearts compared with untreated HS hearts. KATP channel density was 156% higher in myocytes isolated from HS animals compared with control animals. Sulfonylurea receptor 1 protein expression was increased in the left atrial appendage and right atrial appendage of HS animals (415% and 372% of NS animals, respectively). In conclusion, KATP channel activation provides a mechanistic link between salt-induced elevated BP and increased atrial arrhythmia inducibility. The findings of this study have important implications for the treatment and prevention of atrial arrhythmias in the setting of hypertensive heart disease and may lead to new therapeutic approaches. PMID:21724863
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High level of oxygen treatment causes cardiotoxicity with arrhythmias and redox modulation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Chapalamadugu, Kalyan C.; Panguluri, Siva K.; Bennett, Eric S.
2015-01-01
Hyperoxia exposure in mice leads to cardiac hypertrophy and voltage-gated potassium (Kv) channel remodeling. Because redox balance of pyridine nucleotides affects Kv function and hyperoxia alters cellular redox potential, we hypothesized that hyperoxia exposure leads to cardiac ion channel disturbances and redox changes resulting in arrhythmias. In the present study, we investigated the electrical changes and redox abnormalities caused by 72 h hyperoxia treatment in mice. Cardiac repolarization changes were assessed by acquiring electrocardiogram (ECG) and cardiac action potentials (AP). Biochemical assays were employed to identify the pyridine nucleotide changes, Kv1.5 expression and myocardial injury. Hyperoxia treatment caused marked bradycardia,more » arrhythmia and significantly prolonged (ms) the, RR (186.2 ± 10.7 vs. 146.4 ± 6.2), PR (46.8 ± 3.1 vs. 39.3 ± 1.6), QRS (10.8 ± 0.6 vs. 8.5 ± 0.2), QTc (57.1 ± 3.5 vs. 40 ± 1.4) and JT (13.4 ± 2.1 vs. 7.0 ± 0.5) intervals, when compared with normoxia group. Hyperoxia treatment also induced significant increase in cardiac action potential duration (APD) (ex-APD{sub 90}; 73.8 ± 9.5 vs. 50.9 ± 3.1 ms) and elevated levels of serum markers of myocardial injury; cardiac troponin I (TnI) and lactate dehydrogenase (LDH). Hyperoxia exposure altered cardiac levels of mRNA/protein expression of; Kv1.5, Kvβ subunits and SiRT1, and increased ratios of reduced pyridine nucleotides (NADH/NAD and NADPH/NADP). Inhibition of SiRT1 in H9C2 cells using Splitomicin resulted in decreased SiRT1 and Kv1.5 expression, suggesting that SiRT1 may mediate Kv1.5 downregulation. In conclusion, the cardiotoxic effects of hyperoxia exposure involve ion channel disturbances and redox changes resulting in arrhythmias. - Highlights: • Hyperoxia treatment leads to arrhythmia with prolonged QTc and action potential duration. • Hyperoxia treatment alters cardiac pyridine nucleotide [NAD(P)H/NAD(P)] levels. • SiRT1 and Kv1.5 are co-regulated in hyperoxic heart injury. • Hyperoxia may lead to cardiotoxicity.« less
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Romero, Lucía; Carbonell, Beatriz; Trenor, Beatriz; Rodríguez, Blanca; Saiz, Javier; Ferrero, José M
2011-10-01
Several mathematical models of rabbit ventricular action potential (AP) have been proposed to investigate mechanisms of arrhythmias and excitation-contraction coupling. Our study aims at systematically characterizing how ionic current properties modulate the main cellular biomarkers of arrhythmic risk using two widely-used rabbit ventricular models, and comparing simulation results using the two models with experimental data available for rabbit. A sensitivity analysis of AP properties, Ca²⁺ and Na⁺ dynamics, and their rate dependence to variations (±15% and ±30%) in the main transmembrane current conductances and kinetics was performed using the Shannon et al. (2004) and the Mahajan et al. (2008a,b) AP rabbit models. The effects of severe transmembrane current blocks (up to 100%) on steady-state AP and calcium transients, and AP duration (APD) restitution curves were also simulated using both models. Our simulations show that, in both virtual rabbit cardiomyocytes, APD is significantly modified by most repolarization currents, AP triangulation is regulated mostly by the inward rectifier K⁺ current (I(K1)) whereas APD rate adaptation as well as [Na⁺](i) rate dependence is influenced by the Na⁺/K⁺ pump current (I(NaK)). In addition, steady-state [Ca²⁺](i) levels, APD restitution properties and [Ca²⁺](i) rate dependence are strongly dependent on I(NaK), the L-Type Ca²⁺ current (I(CaL)) and the Na⁺/Ca²⁺ exchanger current (I(NaCa)), although the relative role of these currents is markedly model dependent. Furthermore, our results show that simulations using both models agree with many experimentally-reported electrophysiological characteristics. However, our study shows that the Shannon et al. model mimics rabbit electrophysiology more accurately at normal pacing rates, whereas Mahajan et al. model behaves more appropriately at faster rates. Our results reinforce the usefulness of sensitivity analysis for further understanding of cellular electrophysiology and validation of cardiac AP models. Copyright © 2011 Elsevier Ltd. All rights reserved.
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Crataegus extract prolongs action potential duration in guinea-pig papillary muscle.
Müller, A; Linke, W; Zhao, Y; Klaus, W
1996-11-01
Crataegus extract is used in cardiology for the treatment of moderate heart failure (NYHA II). Recently it was shown that Crataegus extract prolongs the refractory period in isolated perfused guinea pig hearts. In order to find out what mechanism is responsible for this prolongation of refractory period, we investigated the effects of Crataegus extract (LI 132) on the action potential of guinea pig papillary muscle with the help of conventional microelectrode techniques. Crataegus extract, when put in a concentration (10 mg/l) capable of inducing an inotropic effect of about 20%, significantly increased action potential duration at all investigated levels of repolarisation. Maximum prolongation was 8.5±2.3 ms, 12.5±2.6 ms and 11.7±2.9 ms at 20%, 50% and 90% repolarisation, respectively (control APD(90): 172±4 ms). Experiments on the time course of recovery of the maximum upstroke velocity (V(max)) of the action potential revealed that Crataegus extract increased the time constant of recovery of V(max) from 8.80±2.33 ms to 22.60±5.77 ms, indicating a weak Class I-like antiarrhythmic action. In addition, we observed a small reduction in V(max). In summary, our results show that Crataegus extract prolongs action potential duration and delays recovery of V(max). We, therefore, suggest that Crataegus extract possesses certain antiarrhythmic properties. Copyright © 1996 Gustav Fischer Verlag · Stuttgart · Jena · New York. Published by Elsevier GmbH.. All rights reserved.
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Optical mapping of optogenetically shaped cardiac action potentials.
Park, Sarah A; Lee, Shin-Rong; Tung, Leslie; Yue, David T
2014-08-19
Light-mediated silencing and stimulation of cardiac excitability, an important complement to electrical stimulation, promises important discoveries and therapies. To date, cardiac optogenetics has been studied with patch-clamp, multielectrode arrays, video microscopy, and an all-optical system measuring calcium transients. The future lies in achieving simultaneous optical acquisition of excitability signals and optogenetic control, both with high spatio-temporal resolution. Here, we make progress by combining optical mapping of action potentials with concurrent activation of channelrhodopsin-2 (ChR2) or halorhodopsin (eNpHR3.0), via an all-optical system applied to monolayers of neonatal rat ventricular myocytes (NRVM). Additionally, we explore the capability of ChR2 and eNpHR3.0 to shape action-potential waveforms, potentially aiding the study of short/long QT syndromes that result from abnormal changes in action potential duration (APD). These results show the promise of an all-optical system to acquire action potentials with precise temporal optogenetics control, achieving a long-sought flexibility beyond the means of conventional electrical stimulation.
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Optical mapping of optogenetically shaped cardiac action potentials
Park, Sarah A.; Lee, Shin-Rong; Tung, Leslie; Yue, David T.
2014-01-01
Light-mediated silencing and stimulation of cardiac excitability, an important complement to electrical stimulation, promises important discoveries and therapies. To date, cardiac optogenetics has been studied with patch-clamp, multielectrode arrays, video microscopy, and an all-optical system measuring calcium transients. The future lies in achieving simultaneous optical acquisition of excitability signals and optogenetic control, both with high spatio-temporal resolution. Here, we make progress by combining optical mapping of action potentials with concurrent activation of channelrhodopsin-2 (ChR2) or halorhodopsin (eNpHR3.0), via an all-optical system applied to monolayers of neonatal rat ventricular myocytes (NRVM). Additionally, we explore the capability of ChR2 and eNpHR3.0 to shape action-potential waveforms, potentially aiding the study of short/long QT syndromes that result from abnormal changes in action potential duration (APD). These results show the promise of an all-optical system to acquire action potentials with precise temporal optogenetics control, achieving a long-sought flexibility beyond the means of conventional electrical stimulation. PMID:25135113
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Song, Weihua; Xiao, Yucheng; Chen, Hanying; Ashpole, Nicole M; Piekarz, Andrew D; Ma, Peilin; Hudmon, Andy; Cummins, Theodore R; Shou, Weinian
2012-01-01
The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of-function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals. PMID:22826127
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Antiarrhythmic effect of IKr activation in a cellular model of LQT3.
Diness, Jonas Goldin; Hansen, Rie Schultz; Nissen, Jakob Dahl; Jespersen, Thomas; Grunnet, Morten
2009-01-01
Long QT syndrome type 3 (LQT3) is an inherited cardiac disorder caused by gain-of-function mutations in the cardiac voltage-gated sodium channel, Na(v)1.5. LQT3 is associated with the polymorphic ventricular tachycardia torsades de pointes (TdP), which can lead to syncope and sudden cardiac death. The sea anemone toxin ATX-II has been shown to inhibit the inactivation of Na(v)1.5, thereby closely mimicking the underlying cause of LQT3 in patients. The hypothesis for this study was that activation of the I(Kr) current could counteract the proarrhythmic effects of ATX-II. Two different activators of I(Kr), NS3623 and mallotoxin (MTX), were used in patch clamp studies of ventricular cardiac myocytes acutely isolated from guinea pig to test the effects of selective I(Kr) activation alone and in the presence of ATX-II. Action potentials were elicited at 1 Hz by current injection and the cells were kept at 32 degrees C to 35 degrees C. NS3623 significantly shortened action potential duration at 90% repolarization (APD(90)) compared with controls in a dose-dependent manner. Furthermore, it reduced triangulation, which is potentially antiarrhythmic. Application of ATX-II (10 nM) was proarrhythmic, causing a profound increase of APD(90) as well as early afterdepolarizations and increased beat-to-beat variability. Two independent I(Kr) activators attenuated the proarrhythmic effects of ATX-II. NS3623 did not affect the late sodium current (I(NaL)) in the presence of ATX-II. Thus, the antiarrhythmic effect of NS3623 is likely to be caused by selective I(Kr) activation. The present data show the antiarrhythmic potential of selective I(Kr) activation in a cellular model of the LQT3 syndrome.
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What Can We Learn about Auditory Processing from Adult Hearing Questionnaires?
Bamiou, Doris-Eva; Iliadou, Vasiliki Vivian; Zanchetta, Sthella; Spyridakou, Chrysa
2015-01-01
Questionnaires addressing auditory disability may identify and quantify specific symptoms in adult patients with listening difficulties. (1) To assess validity of the Speech, Spatial, and Qualities of Hearing Scale (SSQ), the (Modified) Amsterdam Inventory for Auditory Disability (mAIAD), and the Hyperacusis Questionnaire (HYP) in adult patients experiencing listening difficulties in the presence of a normal audiogram. (2) To examine which individual questionnaire items give the worse scores in clinical participants with an auditory processing disorder (APD). A prospective correlational analysis study. Clinical participants (N = 58) referred for assessment because of listening difficulties in the presence of normal audiometric thresholds to audiology/ear, nose, and throat or audiovestibular medicine clinics. Normal control participants (N = 30). The mAIAD, HYP, and the SSQ were administered to a clinical population of nonneurological adults who were referred for auditory processing (AP) assessment because of hearing complaints, in the presence of normal audiogram and cochlear function, and to a sample of age-matched normal-hearing controls, before the AP testing. Clinical participants with abnormal results in at least one ear and in at least two tests of AP (and at least one of these tests to be nonspeech) were classified as clinical APD (N = 39), and the remaining (16 of whom had a single test abnormality) as clinical non-APD (N = 19). The SSQ correlated strongly with the mAIAD and the HYP, and correlation was similar within the clinical group and the normal controls. All questionnaire total scores and subscores (except sound distinction of mAIAD) were significantly worse in the clinical APD versus the normal group, while questionnaire total scores and most subscores indicated greater listening difficulties for the clinical non-APD versus the normal subgroups. Overall, the clinical non-APD group tended to give better scores than the APD in all questionnaires administered. Correlation was strong for the worse-ear gaps-in-noise threshold with the SSQ, mAIAD, and HYP; strong to moderate for the speech in babble and left-ear dichotic digit test scores (at p < 0.01); and weak to moderate for the remaining AP tests except the frequency pattern test that did not correlate. The worse-scored items in all three questionnaires concerned speech-in-noise questions. This is similar to worse-scored items by hearing-impaired participants as reported in the literature. Worse-scored items of the clinical group also included quality aspects of listening questions from the SSQ, which most likely pertain to cognitive aspects of listening, such as ability to ignore other sounds and listening effort. Hearing questionnaires may help assess symptoms of adults with APD. The listening difficulties and needs of adults with APD to some extent overlap with those of hearing-impaired listeners, but there are significant differences. The correlation of the gaps-in-noise and duration pattern (but not frequency pattern) tests with the questionnaire scores indicates that temporal processing deficits may play an important role in clinical presentation. American Academy of Audiology.
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Attachment priming and avoidant personality features as predictors of social-evaluation biases.
Bowles, David P; Meyer, Björn
2008-02-01
Personality research has shown that negativity in social situations (e.g., negative evaluations of others) can be reduced by the activation of participants' sense of attachment security. Individuals with avoidant personality disorder (APD), however, are theoretically less responsive to context or situational cues because of the inflexible nature of their personality disposition. This idea of individual differences in context-responsiveness was tested in a sample of 169 undergraduates who were assessed for APD features and assigned to positive, negative, or neutral attachment priming conditions. More pronounced APD features were associated with more negative responses to vignettes describing potentially distressing social situations. A significant interaction showed that participants with more avoidant features consistently appraised the vignettes relatively more negatively, regardless of priming condition. Those without APD features, by contrast, did not exhibit negative appraisals/evaluations unless negatively primed (curvilinear effect). This effect could not be explained by depression, current mood, or attachment insecurity, all of which related to negative evaluative biases, but none of which related to situation inflexibility. These findings provide empirical support for the notion that negative information-processing is unusually inflexible and context-unresponsive among individuals with more pronounced features of APD.
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Jiang, X Y; Zhou, C M; Li, D M; Zhang, K J
1996-01-01
The effects of DSPM-Cl on ECG in rats, on the dose-effect curve in guinea pig left atria and on the fast action potential (AP), high-K+ depolarized slow action potential (SAP) in guinea pigs papillary muscle were examined electrophysiologically. DSPM-Cl (2 mg.kg-1) showed significant nagative frequency, negative conductivity effect, and prolonged the PP and PR interval. DSPM-CI (30-50 mumol.L-1) was shown to inhibit left atria contractility and shift the concentration-response curve of Iso and CaCl2 to the right with PD2' values of 4.60 and 4.13, respectively. In addition, DSPM-Cl was found to prolong the duration of action potential 90 (APD90) and effective refractory period (ERP), and decrease the maximal upstroke velocity (Vmax) in K(+)-depolarized guinea pigs papillary muscles. The results suggest that, like verpamil, DSPM-Cl might be a calcium antagonist.
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Tomlin, Danielle; Moore, David R.; Dillon, Harvey
2015-01-01
Objectives: In this study, the authors assessed the potential utility of a recently developed questionnaire (Evaluation of Children’s Listening and Processing Skills [ECLiPS]) for supporting the clinical assessment of children referred for auditory processing disorder (APD). Design: A total of 49 children (35 referred for APD assessment and 14 from mainstream schools) were assessed for auditory processing (AP) abilities, cognitive abilities, and symptoms of listening difficulty. Four questionnaires were used to capture the symptoms of listening difficulty from the perspective of parents (ECLiPS and Fisher’s auditory problem checklist), teachers (Teacher’s Evaluation of Auditory Performance), and children, that is, self-report (Listening Inventory for Education). Correlation analyses tested for convergence between the questionnaires and both cognitive and AP measures. Discriminant analyses were performed to determine the best combination of tests for discriminating between typically developing children and children referred for APD. Results: All questionnaires were sensitive to the presence of difficulty, that is, children referred for assessment had significantly more symptoms of listening difficulty than typically developing children. There was, however, no evidence of more listening difficulty in children meeting the diagnostic criteria for APD. Some AP tests were significantly correlated with ECLiPS factors measuring related abilities providing evidence for construct validity. All questionnaires correlated to a greater or lesser extent with the cognitive measures in the study. Discriminant analysis suggested that the best discrimination between groups was achieved using a combination of ECLiPS factors, together with nonverbal Intelligence Quotient (cognitive) and AP measures (i.e., dichotic digits test and frequency pattern test). Conclusions: The ECLiPS was particularly sensitive to cognitive difficulties, an important aspect of many children referred for APD, as well as correlating with some AP measures. It can potentially support the preliminary assessment of children referred for APD. PMID:26002277
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Washburn, Jason J.; Romero, Erin Gregory; Welty, Leah J.; Abram, Karen M.; Teplin, Linda A.; McClelland, Gary M.; Paskar, Leah D.
2009-01-01
Antisocial personality disorder (APD) is a serious public and mental health concern. Understanding how well conduct disorder (CD) and other mental disorders predict the development of APD among youth involved in the juvenile justice system is critical for prevention. This study used a stratified random sample of 1112 detained youth to examine the development of APD at a three-year follow-up interview. Nearly one fifth of male juvenile detainees later developed APD; approximately one quarter of male juvenile detainees with CD at baseline later developed APD. Significantly more males than females developed APD; no differences were found by race/ethnicity. Having five or more symptoms of CD, dysthymia, alcohol use disorder, or generalized anxiety disorder was significantly associated with developing modified APD (M-APD; APD without the CD requirement). Some disorders were strong predictors of APD; however, none were adequate screeners for identifying which detainees would later develop M-APD. The findings of this study have implications for interventions and further research in developmental psychopathology. PMID:17469880
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Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function
Vinish, Monika; Elnabawi, Ahmed; Milstein, Jean A.; Burke, Jesse S.; Kallevang, Jonathan K.; Turek, Kevin C.; Lansink, Carien S.; Merchenthaler, Istvan; Bailey, Aileen M.; Kolb, Bryan; Cheer, Joseph F.; Frost, Douglas O.
2018-01-01
Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D2 receptors ; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28–49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D1 receptor binding was reduced, D2 binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients. PMID:23351612
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Development of high-sensitivity SWIR APD receivers
NASA Astrophysics Data System (ADS)
Bai, Xiaogang; Yuan, Ping; Chang, James; Sudharsanan, Rengarajan; Krainak, Michael; Yang, Guangning; Sun, Xiaoli; Lu, Wei
2013-06-01
Emerging short wavelength infrared (SWIR) LIght Detection And Ranging (LIDAR) and long range laser rangefinder systems, require large optical aperture avalanche photodiodes (APDs) receivers with high sensitivity and high bandwidth. A large optical aperture is critical to increase the optical coupling efficiency and extend the LIDAR sensing range of the above systems. Both APD excess noise and transimpedance amplifier (TIA) noise need to be reduced in order to achieve high receiver sensitivity. The dark current and capacitance of large area APDs increase with APD aperture and thus limit the sensitivity and bandwidth of receivers. Spectrolab has been developing low excess noise InAlAs/InGaAs APDs with impact ionization engineering (I2E) designs for many years and has demonstrated APDs with optical gain over 100 utilizing multiple period I2E structures in the APD multiplier. These high gain I2E APDs have an excess noise factor less than 0.15. With an optical aperture of 200 μm, low excess noise multiple periods I2E APDs have capacitances about 1.7 pF. In addition, optical gains of InAlAs based APDs show very little temperature dependence and will enable APD photoreceivers without thermal electric cooling.
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Modulation of KCNQ1 alternative splicing regulates cardiac IKs and action potential repolarization.
Lee, Hsiang-Chun; Rudy, Yoram; Po-Yuan, Phd; Sheu, Sheng-Hsiung; Chang, Jan-Gowth; Cui, Jianmin
2013-08-01
Slow delayed-rectifier potassium current (IKs) channels, made of the pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining action potential duration (APD) in cardiac myocytes. The consequences of drug-induced KCNQ1 splice alteration remain unknown. To study the modulation of KCNQ1 alternative splicing by amiloride and the consequent changes in IKs and action potentials (APs) in ventricular myocytes. Canine endocardial, midmyocardial, and epicardial ventricular myocytes were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing factors were quantified by using the reverse transcriptase-polymerase chain reaction and Western blot. The effect of amiloride-induced changes in the KCNQ1b/total KCNQ1 ratio on AP was measured by using whole-cell patch clamp with and without isoproterenol. With 50 μmol/L of amiloride for 6 hours, KCNQ1a at transcriptional and translational levels increased in midmyocardial myocytes but decreased in endo- and epicardial myocytes. Likewise, changes in splicing factors in midmyocardial were opposite to that in endo- and epicardial myocytes. In midmyocardial myocytes amiloride shortened APD and decreased isoproterenol-induced early afterdepolarizations significantly. The same amiloride-induced effects were demonstrated by using human ventricular myocyte model for AP simulations under beta-adrenergic stimulation. Moreover, amiloride reduced the transmural dispersion of repolarization in pseudo-electrocardiogram. Amiloride regulates IKs and APs with transmural differences and reduces arrhythmogenicity through the modulation of KCNQ1 splicing. We suggested that the modulation of KCNQ1 splicing may help prevent arrhythmia. Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
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Yan, Meng; Feng, Lifang; Shi, Yanhui; Wang, Junnan; Liu, Yan; Li, Fengmei; Li, Baoxin
2017-08-01
Arsenic trioxide (As2O3) has been verified as a breakthrough in the management of acute promyelocytic leukemia in recent decades. However, cardiotoxicity, especially long QT syndrome (LQTS) has become the most important issue during As2O3 treatment. The characterized mechanisms behind this adverse effect are inhibition of cardiac hERG channel trafficking and increase of cardiac calcium currents. In our study, we found a new pathway underlying As2O3-induced cardiotoxicity that As2O3 accelerates lysosomal degradation of hERG on plasma membrane after using brefeldin A (BFA) to block protein trafficking. Then we explored pharmacological rescue strategies on As2O3-induced LQTS, and found that 4 therapeutic agents exert rescue efficacy via 3 different pathways: fexofenadine and astemizole facilitate hERG trafficking via promotion of channel-chaperone formation after As2O3 incubation; ranolazine slows hERG degradation in the presence of As2O3; and resveratrol shows significant attenuation on calcium current increase triggered by As2O3. Moreover, we used human-induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) to evaluate the rescue effects of the above agents on As2O3-induced prolongation of action potential duration (APD) and demonstrated that fexofenadine and resveratrol significantly ameliorate the prolonged APD. These observations suggested that pharmacological chaperone like fexofenadine and resveratrol might have the potential to protect against the cardiotoxicity of As2O3. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Washburn, Jason J; Romero, Erin Gregory; Welty, Leah J; Abram, Karen M; Teplin, Linda A; McClelland, Gary M; Paskar, Leah D
2007-04-01
Antisocial personality disorder (APD) is a serious public and mental health concern. Understanding how well conduct disorder (CD) and other mental disorders predict the development of APD among youths involved in the juvenile justice system is critical for prevention. The authors used a stratified random sample of 1,112 detained youths to examine the development of APD at a 3-year follow-up interview. Nearly one fifth of male juvenile detainees later developed APD; approximately one quarter of male juvenile detainees with CD at baseline later developed APD. Significantly more males than females developed APD; no differences were found by race/ethnicity. Having 5 or more symptoms of CD, dysthymia, alcohol use disorder, or generalized anxiety disorder was significantly associated with developing modified APD (M-APD; APD without the CD requirement). Some disorders were strong predictors of APD; however, none were adequate screeners for identifying which detainees would later develop M-APD. The findings of this study have implications for interventions and further research in developmental psychopathology. Copyright 2007 APA, all rights reserved.
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Stavrinos, Georgios; Iliadou, Vassiliki-Maria; Edwards, Lindsey; Sirimanna, Tony; Bamiou, Doris-Eva
2018-01-01
Measures of attention have been found to correlate with specific auditory processing tests in samples of children suspected of Auditory Processing Disorder (APD), but these relationships have not been adequately investigated. Despite evidence linking auditory attention and deficits/symptoms of APD, measures of attention are not routinely used in APD diagnostic protocols. The aim of the study was to examine the relationship between auditory and visual attention tests and auditory processing tests in children with APD and to assess whether a proposed diagnostic protocol for APD, including measures of attention, could provide useful information for APD management. A pilot study including 27 children, aged 7–11 years, referred for APD assessment was conducted. The validated test of everyday attention for children, with visual and auditory attention tasks, the listening in spatialized noise sentences test, the children's communication checklist questionnaire and tests from a standard APD diagnostic test battery were administered. Pearson's partial correlation analysis examining the relationship between these tests and Cochrane's Q test analysis comparing proportions of diagnosis under each proposed battery were conducted. Divided auditory and divided auditory-visual attention strongly correlated with the dichotic digits test, r = 0.68, p < 0.05, and r = 0.76, p = 0.01, respectively, in a sample of 20 children with APD diagnosis. The standard APD battery identified a larger proportion of participants as having APD, than an attention battery identified as having Attention Deficits (ADs). The proposed APD battery excluding AD cases did not have a significantly different diagnosis proportion than the standard APD battery. Finally, the newly proposed diagnostic battery, identifying an inattentive subtype of APD, identified five children who would have otherwise been considered not having ADs. The findings show that a subgroup of children with APD demonstrates underlying sustained and divided attention deficits. Attention deficits in children with APD appear to be centred around the auditory modality but further examination of types of attention in both modalities is required. Revising diagnostic criteria to incorporate attention tests and the inattentive type of APD in the test battery, provides additional useful data to clinicians to ensure careful interpretation of APD assessments. PMID:29441033
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Benecke, Cord; Huber, Dorothea; Staats, Hermann; Zimmermann, Johannes; Henkel, Miriam; Deserno, Heinrich; Wiegand-Grefe, Silke; Schauenburg, Henning
2016-09-01
Anxiety disorders, most notably panic disorders and agoraphobia, are common mental disorders, and there is a high comorbidity with personality disorders. Randomized controlled trails addressing this highly relevant group of patients are missing. The multicenter Anxiety and Personality Disorders (APD) study investigates 200 patients with panic disorder and/or agoraphobia with comorbid personality disorder in a randomized control-group comparison of psychoanalytic therapy (PT) and cognitive behavioral therapy (CBT), including 100 patients in each group. Each patient will be examined over a period of six years, regardless of the duration of the individual treatment. The main issues that are addressed in this study are the comparison of the efficacy of PT and CBT in this special patient population, the comparison of the sustainability of the effects of PT and CBT, the comparison of the long-term cost-benefit-ratios of PT and CBT as well as the investigation of prescriptive patient characteristics for individualized treatment recommendations (differential indication). The APD study compares efficacy, sustainability, and cost-benefit-ratios of CBT and PT for anxiety plus personality disorders in a randomized controlled trail. The study design meets the requirements for an efficacy study for PT, which were recently defined. Current Controlled Trials ISRCTN12449681.
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Cardiac tissue slices: preparation, handling, and successful optical mapping.
Wang, Ken; Lee, Peter; Mirams, Gary R; Sarathchandra, Padmini; Borg, Thomas K; Gavaghan, David J; Kohl, Peter; Bollensdorff, Christian
2015-05-01
Cardiac tissue slices are becoming increasingly popular as a model system for cardiac electrophysiology and pharmacology research and development. Here, we describe in detail the preparation, handling, and optical mapping of transmembrane potential and intracellular free calcium concentration transients (CaT) in ventricular tissue slices from guinea pigs and rabbits. Slices cut in the epicardium-tangential plane contained well-aligned in-slice myocardial cell strands ("fibers") in subepicardial and midmyocardial sections. Cut with a high-precision slow-advancing microtome at a thickness of 350 to 400 μm, tissue slices preserved essential action potential (AP) properties of the precutting Langendorff-perfused heart. We identified the need for a postcutting recovery period of 36 min (guinea pig) and 63 min (rabbit) to reach 97.5% of final steady-state values for AP duration (APD) (identified by exponential fitting). There was no significant difference between the postcutting recovery dynamics in slices obtained using 2,3-butanedione 2-monoxime or blebistatin as electromechanical uncouplers during the cutting process. A rapid increase in APD, seen after cutting, was caused by exposure to ice-cold solution during the slicing procedure, not by tissue injury, differences in uncouplers, or pH-buffers (bicarbonate; HEPES). To characterize intrinsic patterns of CaT, AP, and conduction, a combination of multipoint and field stimulation should be used to avoid misinterpretation based on source-sink effects. In summary, we describe in detail the preparation, mapping, and data analysis approaches for reproducible cardiac tissue slice-based investigations into AP and CaT dynamics. Copyright © 2015 the American Physiological Society.
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Cardiac tissue slices: preparation, handling, and successful optical mapping
Wang, Ken; Lee, Peter; Mirams, Gary R.; Sarathchandra, Padmini; Borg, Thomas K.; Gavaghan, David J.; Kohl, Peter
2015-01-01
Cardiac tissue slices are becoming increasingly popular as a model system for cardiac electrophysiology and pharmacology research and development. Here, we describe in detail the preparation, handling, and optical mapping of transmembrane potential and intracellular free calcium concentration transients (CaT) in ventricular tissue slices from guinea pigs and rabbits. Slices cut in the epicardium-tangential plane contained well-aligned in-slice myocardial cell strands (“fibers”) in subepicardial and midmyocardial sections. Cut with a high-precision slow-advancing microtome at a thickness of 350 to 400 μm, tissue slices preserved essential action potential (AP) properties of the precutting Langendorff-perfused heart. We identified the need for a postcutting recovery period of 36 min (guinea pig) and 63 min (rabbit) to reach 97.5% of final steady-state values for AP duration (APD) (identified by exponential fitting). There was no significant difference between the postcutting recovery dynamics in slices obtained using 2,3-butanedione 2-monoxime or blebistatin as electromechanical uncouplers during the cutting process. A rapid increase in APD, seen after cutting, was caused by exposure to ice-cold solution during the slicing procedure, not by tissue injury, differences in uncouplers, or pH-buffers (bicarbonate; HEPES). To characterize intrinsic patterns of CaT, AP, and conduction, a combination of multipoint and field stimulation should be used to avoid misinterpretation based on source-sink effects. In summary, we describe in detail the preparation, mapping, and data analysis approaches for reproducible cardiac tissue slice-based investigations into AP and CaT dynamics. PMID:25595366
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Chen, Wei-Jan; Yeh, Yung-Hsin; Lin, Kwang-Huei; Chang, Gwo-Jyh; Kuo, Chi-Tai
2011-03-01
Atrial fibrillation (AF) is a common complication in hyperthyroidism. Earlier studies demonstrate that thyroid hormone decreases L-type calcium channel (LCC) current expression with resultant shortening of action potential duration (APD), providing a substrate for AF. The aim of this study was to investigate the potential mechanism underlying the regulatory effect of thyroid hormone on LCC. In a hyperthyroid rat model, thyroid hormone (triiodothyronine [T3]) administration down-regulated atrial LCC expression. In vitro, treatment of murine atrial myocytes (HL-1) with T3 decreased the expression of LCC and its current, resulting in abbreviation of APD. Furthermore, T3 inhibited the activation of cyclic AMP response element (CRE)-binding protein (CREB), including phosphorylation at Ser133 and its nuclear translocation. Transient transfection studies in HL-1 cells indicated that T3 reduced LCC promoter activity. Deletion and mutation analysis of the LCC promoter region along with chromatin immunoprecipitation using anti-CREB antibody showed that CRE was essential for T3-mediated LCC gene expression. Transfection of dominant-negative CREB (mutated Ser133) and mutant thyroid hormone receptor (TR, mutated Cys51) abolished the T3-dependent effects, suggesting an association between both transcriptional factors. Co-immunoprecipitation documented an increased binding of TR with CREB after T3 treatment. The transcriptional cross-talk 3 between TR and CREB bound to CRE mediates T3-inhibited CREB activity and LCC expression. Thyroid hormone-induced TR binding of CREB inhibits CREB activity and LCC current expression, which may contribute to AF. These findings provide an important mechanistic insight into hyperthyroidism-induced AF.
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Reduction of atrial fibrillation by Tanshinone IIA in chronic heart failure.
He, Zhifeng; Sun, Changzheng; Xu, Yi; Cheng, Dezhi
2016-12-01
The aim of the present study was to confirm the effect of Tanshinone IIA (TAN) on the prevention of AF in chronic heart failure (CHF), and to elucidate the underlying electrophysiological mechanisms for the antiarrhythmic effects of TAN at the level of the atrium in an experimental model of CHF. In 10 female rabbits, CHF was induced by rapid ventricular pacing, leading to a significant decrease in ejection fraction in the presence of a dilated left ventricle and atrial enlargement. Twelve rabbits were sham-operated and served as controls. Isolated hearts were perfused using the Langendorff method. Burst pacing was used to induce AF. Monophasic action potential recordings showed an increase of atrial action potential duration (aAPD) and effective refractory period (aERP) in CHF hearts compared with sham hearts. Infusion of acetylcholine (1μm) and isoproterenol (1μm) led to AF in all failing hearts and in 11 sham hearts. Simultaneous infusion of TAN (10μm) remarkably reduced inducibility of AF in 50% of sham and 50% of failing hearts. TAN had no effect on aAPD but significantly increased aERP, leading to a marked increase in atrial post-repolarization refractoriness. Moreover, TAN application moderately increased interatrial conduction time. TAN has been shown to be effective in reducing the inducibility of AF in an experimental model of AF. The antiarrhythmic effect is mainly due to prolongations of atrial post-repolarization refractoriness and a moderate increase in interatrial conduction time. Copyright © 2016. Published by Elsevier Masson SAS.
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An, Meng-Yao; Sun, Kai; Li, Yan; Pan, Ying-Ying; Yin, Yong-Qiang; Kang, Yi; Sun, Tao; Wu, Hong; Gao, Wei-Zhen; Lou, Jian-Shi
2018-03-01
Short QT syndrome (SQTS) is a genetic arrhythmogenic disease that can cause malignant arrhythmia and sudden cardiac death. The current therapies for SQTS have application restrictions. We previously found that Mg· (NH 2 CH 2 CH 2 SO 3 )2· H 2 O, a taurine-magnesium coordination compound (TMCC) exerted anti-arrhythmic effects with low toxicity. In this study we established 3 different models to assess the potential anti-arrhythmic effects of TMCC on type 2 short QT syndrome (SQT2). In Langendorff guinea pig-perfused hearts, perfusion of pinacidil (20 μmol/L) significantly shortened the QT interval and QTpeak and increased rTp-Te (P<0.05 vs control). Subsequently, perfusion of TMCC (1-4 mmol/L) dose-dependently increased the QT interval and QTpeak (P<0.01 vs pinacidil). TMCC perfusion also reversed the rTp-Te value to the normal range. In guinea pig ventricular myocytes, perfusion of trapidil (1 mmol/L) significantly shortened the action potential duration at 50% (APD 50 ) and 90% repolarization (APD 90 ), which was significantly reversed by TMCC (0.01-1 mmol/L, P<0.05 vs trapidil). In HEK293 cells that stably expressed the outward delayed rectifier potassium channels (I Ks ), perfusion of TMCC (0.01-1 mmol/L) dose-dependently inhibited the IKs current with an IC 50 value of 201.1 μmol/L. The present study provides evidence that TMCC can extend the repolarization period and inhibit the repolarizing current, I Ks , thereby representing a therapeutic candidate for ventricular arrhythmia in SQT2.
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Change of short-term memory effect in acute ischemic ventricular myocardium: a computational study.
Mei, Xi; Wang, Jing; Zhang, Hong; Liu, Zhi-cheng; Zhang, Zhen-xi
2014-02-01
The ionic mechanism of change in short-term memory (STM) during acute myocardial ischemia has not been well understood. In this paper, an advanced guinea pig ventricular model developed by Luo and Rudy was used to investigate STM property of ischemic ventricular myocardium. STM response was calculated by testing the time to reach steady-state action potential duration (APD) after an abrupt shortening of basic cycling length (BCL) in the pacing protocol. Electrical restitution curves (RCs), which can simultaneously visualize multiple aspects of APD restitution and STM, were obtained from dynamic and local S1S2 restitution portrait (RP), which consist of a longer interval stimulus (S1) and a shorter interval stimulus (S2). The angle between dynamic RC and local S1S2 RC reflects the amount of STM. Our results indicated that compared with control (normal) condition, time constant of STM response in the ischemic condition decreased significantly. Meanwhile the angle which reflects STM amount is less in ischemic model than that in control model. By tracking the effect of ischemia on intracellular ion concentration and membrane currents, we declared that changes in membrane currents caused by ischemia exert subtle influences on STM; it is only the decline of intracellular calcium concentration that give rise to the most decrement of STM. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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Personality functioning in patients with avoidant personality disorder and social phobia.
Eikenaes, Ingeborg; Hummelen, Benjamin; Abrahamsen, Gun; Andrea, Helene; Wilberg, Theresa
2013-12-01
Avoidant personality disorder (APD) and social phobia (SP) are closely related, such that they are suggested to represent different severity levels of one social anxiety disorder. This cross-sectional study aimed to compare patients with APD to patients with SP, with particular focus on personality dysfunction. Ninety-one adult patients were examined by diagnostic interviews and self-report measures, including the Index of Self-Esteem and the Severity Indices of Personality Problems. Patients were categorized in three groups; SP without APD (n = 20), APD without SP (n = 15), and APD with SP (n = 56). Compared to patients with SP without APD, patients with APD reported more symptom disorders, psychosocial problems, criteria of personality disorders, and personality dysfunction regarding self-esteem, identity and relational problems. These results indicate that APD involves more severe and broader areas of personality dysfunction than SP, supporting the conceptualization of APD as a personality disorder as proposed for DSM-5.
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Zhang, Yuanyuan; Yue, Dongbei; Liu, Jianguo; Lu, Peng; Wang, Ying; Liu, Jing; Nie, Yongfeng
2012-06-30
Characteristics of non-methane organic compounds (NMOCs) emissions during the anaerobic decomposition of untreated (APD-0) and four aerobically pretreated (APD-20, APD-39, APD-49, and APD-63) samples of municipal solid waste (MSW) were investigated in laboratory. The cumulative mass of the NMOCs of APD-20, APD-39, APD-49, and APD-63 accounted for 15%, 9%, 16%, and 15% of that of APD-0, respectively. The intensities of the NMOC emissions calculated by dividing the cumulative NMOC emissions by the quantities of organic matter removed (Q(VS)) decreased from 4.1 mg/kg Q(VS) for APD-0 to 0.8-3.4 mg/kg Q(VS) for aerobically pretreated MSW. The lipid and starch contents might have significant impact on the intensity of the NMOC emissions. Alkanes dominated the NMOCs released from the aerobically pretreated MSW, while oxygenated compounds were the chief component of the NMOCs generated from untreated MSW. Aerobic pretreatment of MSW prior to landfilling reduces the organic content of the waste and the intensity of the NMOC emissions, and increases the odor threshold, thereby reducing the environmental impact of landfills. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Gómez-Hurtado, Nieves; Domínguez-Rodríguez, Alejandro; Mateo, Philippe; Fernández-Velasco, María; Val-Blasco, Almudena; Aizpún, Rafael; Sabourin, Jessica; Gómez, Ana María; Benitah, Jean-Pierre; Delgado, Carmen
2017-07-01
Leptin, is a 16 kDa pleiotropic peptide not only primarily secreted by adipocytes, but also produced by other tissues, including the heart. Controversy exists regarding the adverse and beneficial effects of leptin on the heart We analysed the effect of a non-hypertensive dose of leptin on cardiac function, [Ca 2+ ] i handling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias, both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction. We find that leptin activates mechanisms that contribute to cardiac dysfunction under physiological conditions. However, after the establishment of pressure overload, an increase in leptin levels has protective cardiac effects with respect to rescuing the cellular heart failure phenotype. These beneficial effects of leptin involve restoration of action potential duration via normalization of transient outward potassium current and sarcoplasmic reticulum Ca 2+ content via rescue of control sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase levels and ryanodine receptor function modulation, leading to normalization of Ca 2+ handling parameters. Leptin, is a 16 kDa pleiotropic peptide not only primary secreted by adipocytes, but also produced by other tissues, including the heart. Evidence indicates that leptin may have either adverse or beneficial effects on the heart. To obtain further insights, in the present study, we analysed the effect of leptin treatment on cardiac function, [Ca 2+ ] i handling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias, both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction (TAC). Three weeks after surgery, animals received either leptin (0.36 mg kg -1 day -1 ) or vehicle via osmotic minipumps for 3 weeks. Echocardiographic measurements showed that, although leptin treatment was deleterious on cardiac function in sham, leptin had a cardioprotective effect following TAC. [Ca 2+ ] i transient in cardiomyocytes followed similar pattern. Patch clamp experiments showed prolongation of action potential duration (APD) in TAC and leptin-treated sham animals, whereas, following TAC, leptin reduced the APD towards control values. APD variations were associated with decreased transient outward potassium current and Kv4.2 and KChIP2 protein expression. TAC myocytes showed a higher incidence of triggered activities and spontaneous Ca 2+ waves. These proarrhythmic manifestations, related to Ca 2+ /calmodulin-dependent protein kinase II and ryanodine receptor phosphorylation, were reduced by leptin. The results of the present study demonstrate that, although leptin treatment was deleterious on cardiac function in control animals, leptin had a cardioprotective effect following TAC, normalizing cardiac function and reducing arrhythmogeneity at the cellular level. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.
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Stretch-dependent slow force response in isolated rabbit myocardium is Na+ dependent.
von Lewinski, Dirk; Stumme, Burkhard; Maier, Lars S; Luers, Claus; Bers, Donald M; Pieske, Burkert
2003-03-15
Stretch induces functional and trophic effects in mammalian myocardium via various signal transduction pathways. We tested stretch signal transduction on immediate and slow force response (SFR) in rabbit myocardium. Experiments were performed in isolated right ventricular muscles from adult rabbit hearts (37 degrees C, 1 Hz stimulation rate, bicarbonate-buffer). Muscles were rapidly stretched from 88% of optimal length (L88) to near optimal length (L98) for functional analysis. The resulting immediate and slow increases in twitch force (first phase and SFR, respectively) were assessed at reduced [Na+]o or without and with blockade of stretch activated ion channels (SACs), angiotensin-II (AT1) receptors, endothelin-A (ET(A)) receptors, Na+/H+-exchange (NHE1), reverse mode Na+/Ca2+-exchange (NCX), or Na+/K+-ATPase. The effects of stretch on sarcoplasmic reticulum Ca2+-load were characterized using rapid cooling contractures (RCCs). Intracellular pH was measured in BCECF-AM loaded muscles, and action potential duration (APD) was assessed using floating electrodes. On average, force increased to 216+/-8% of the pre-stretch value during the immediate phase, followed by a further increase to 273+/-10% during the SFR (n=81). RCCs significantly increased during SFR, whereas pH and APD did not change. Neither inhibition of SACs, AT1, or ET(A) receptors affected the stretch-dependent immediate phase nor SFR. In contrast, SFR was reduced by NHE inhibition and almost completely abolished by reduced [Na+]o or inhibition of reverse-mode NCX, whereas increased SFR was seen after raising [Na+]i by Na+/K+-ATPase inhibition. The data demonstrate the existence of a delayed, Na+- and Ca2+-dependent but pH and APD independent SFR to stretch in rabbit myocardium. This inotropic response appears to be independent of autocrine/paracrine AT1 or ET(A) receptor activation, but mediated through stretch-induced activation of NHE and reverse mode NCX.
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Single-Photon-Sensitive HgCdTe Avalanche Photodiode Detector
NASA Technical Reports Server (NTRS)
Huntington, Andrew
2013-01-01
The purpose of this program was to develop single-photon-sensitive short-wavelength infrared (SWIR) and mid-wavelength infrared (MWIR) avalanche photodiode (APD) receivers based on linear-mode HgCdTe APDs, for application by NASA in light detection and ranging (lidar) sensors. Linear-mode photon-counting APDs are desired for lidar because they have a shorter pixel dead time than Geiger APDs, and can detect sequential pulse returns from multiple objects that are closely spaced in range. Linear-mode APDs can also measure photon number, which Geiger APDs cannot, adding an extra dimension to lidar scene data for multi-photon returns. High-gain APDs with low multiplication noise are required for efficient linear-mode detection of single photons because of APD gain statistics -- a low-excess-noise APD will generate detectible current pulses from single photon input at a much higher rate of occurrence than will a noisy APD operated at the same average gain. MWIR and LWIR electron-avalanche HgCdTe APDs have been shown to operate in linear mode at high average avalanche gain (M > 1000) without excess multiplication noise (F = 1), and are therefore very good candidates for linear-mode photon counting. However, detectors fashioned from these narrow-bandgap alloys require aggressive cooling to control thermal dark current. Wider-bandgap SWIR HgCdTe APDs were investigated in this program as a strategy to reduce detector cooling requirements.
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Feifel, D.; Shilling, P. D.; Melendez, G.
2014-01-01
Our laboratory and others have reported that Brattleboro (BRAT) rats, a Long Evans (LE) strain with a single gene mutation, have inherent deficits in prepulse inhibition (PPI) homologous to those observed in schizophrenia patients and that these deficits are reversed by antipsychotic drugs (APDs). To further evaluate the potential predictive validity of BRAT rat PPI for APDs, we compared the effects of acute subcutaneous administration of the typical APD chlorpromazine to that of three psychotropic drugs without antipsychotic efficacy, the antidepressant imipramine, the anxiolytic diazepam and the anticonvulsant mood stabilizer valproic acid on male and female BRAT rat PPI. Male and female BRAT rats exhibited baseline (saline treatment) PPI that was not different from each other (21.1 % and 21.3 %, respectively) and low compared to those historically exhibited by LE rats (approximately 59 %). Chlorpromazine facilitated PPI in male and female BRAT rats, whereas imipramine, diazepam, and valproic acid had no significant effect on PPI. These results suggest that PPI in the BRAT rat responds specifically to drugs with APD efficacy but not psychotropic drugs of different therapeutic families. PMID:21106605
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Application of simple negative feedback model for avalanche photodetectors investigation
NASA Astrophysics Data System (ADS)
Kushpil, V. V.
2009-10-01
A simple negative feedback model based on Miller's formula is used to investigate the properties of Avalanche Photodetectors (APDs). The proposed method can be applied to study classical APD as well as new type of devices, which are operating in the Internal Negative Feedback (INF) regime. The method shows a good sensitivity to technological APD parameters making it possible to use it as a tool to analyse various APD parameters. It also allows better understanding of the APD operation conditions. The simulations and experimental data analysis for different types of APDs are presented.
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Hoeker, Gregory S.; Hood, Ashleigh R.; Katra, Rodolphe P.; Poelzing, Steven; Pogwizd, Steven M.
2014-01-01
Cardioprotection in females, as observed in the setting of heart failure, has been attributed to sex differences in intracellular calcium handling and its modulation by β-adrenergic signaling. However, further studies examining sex differences in β-adrenergic responsiveness have yielded inconsistent results and have mostly been limited to studies of contractility, ion channel function, or calcium handling alone. Given the close interaction of the action potential (AP) and intracellular calcium transient (CaT) through the process of excitation-contraction coupling, the need for studies exploring the relationship between agonist-induced AP and calcium handling changes in female and male hearts is evident. Thus, the aim of this study was to use optical mapping to examine sex differences in ventricular APs and CaTs measured simultaneously from Langendorff-perfused hearts isolated from naïve adult rabbits during β-adrenergic stimulation. The non-selective β-agonist isoproterenol (Iso) decreased AP duration (APD90), CaT duration (CaD80), and the decay constant of the CaT (τ) in a dose-dependent manner (1–316.2 nM), with a plateau at doses ≥31.6 nM. The Iso-induced changes in APD90 and τ (but not CaD80) were significantly smaller in female than male hearts. These sex differences were more significant at faster (5.5 Hz) than resting rates (3 Hz). Treatment with Iso led to the development of spontaneous calcium release (SCR) with a dose threshold of 31.6 nM. While SCR occurrence was similar in female (49%) and male (53%) hearts, the associated ectopic beats had a lower frequency of occurrence (16% versus 40%) and higher threshold (100 nM versus 31.6 nM) in female than male hearts (p<0.05). In conclusion, female hearts had a decreased capacity to respond to β-adrenergic stimulation, particularly under conditions of increased demand (i.e. faster pacing rates and “maximal” levels of Iso effects), however this reduced β-adrenergic responsiveness of female hearts was associated with reduced arrhythmic activity. PMID:25340795
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Arad, Michal; Weiner, Ina
2010-06-01
Women with schizophrenia have later onset and better response to antipsychotic drugs (APDs) than men during reproductive years, but the menopausal period is associated with increased symptom severity and reduced treatment response. Estrogen replacement therapy has been suggested as beneficial but clinical data are inconsistent. Latent inhibition (LI), the capacity to ignore irrelevant stimuli, is a measure of selective attention that is disrupted in acute schizophrenia patients and in rats and humans treated with the psychosis-inducing drug amphetamine and can be reversed by typical and atypical APDs. Here we used amphetamine (1 mg/kg)-induced disrupted LI in ovariectomized rats to model low levels of estrogen along with hyperfunction of the dopaminergic system that may be occurring in menopausal psychosis, and tested the efficacy of APDs and estrogen in reversing disrupted LI. 17beta-Estradiol (50, 150 microg/kg), clozapine (atypical APD; 5, 10 mg/kg), and haloperidol (typical APD; 0.1, 0.3 mg/kg) effectively reversed amphetamine-induced LI disruption in sham rats, but were much less effective in ovariectomized rats; 17beta-estradiol and clozapine were effective only at high doses (150 microg/kg and 10 mg/kg, respectively), whereas haloperidol failed at both doses. Haloperidol and clozapine regained efficacy if coadministered with 17beta-estradiol (50 microg/kg, an ineffective dose). Reduced sensitivity to dopamine (DA) blockade coupled with spared/potentiated sensitivity to DA stimulation after ovariectomy may provide a novel model recapitulating the combination of increased vulnerability to psychosis with reduced response to APD treatment in female patients during menopause. In addition, our data show that 17beta-estradiol exerts antipsychotic activity.
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Do antipsychotic drugs increase seizure frequency in epilepsy patients?
Okazaki, Mitsutoshi; Adachi, Naoto; Akanuma, Nozomi; Hara, Koichiro; Ito, Masumi; Kato, Masaaki; Onuma, Teiichi
2014-11-01
To investigate whether addition of antipsychotic drugs (APD) would increase seizure frequency in epilepsy patients who were already treated with anti-epileptic drugs (AED), we compared a one-year seizure control outcome in 150 epilepsy patients with APD treatment for psychiatric conditions and 309 epilepsy patients without APD treatment matched for ages at epilepsy onset and the baseline evaluation and types of epilepsy. The seizure frequency was recorded at the baseline (immediately before the start of APD) and after the 1st, 3rd, 6th and 12th months. The seizure outcome at each of the four follow-up points was compared with the baseline. The seizure outcome was compared between the two groups as a whole and according to the types of epilepsy (idiopathic generalized and partial epilepsies). In the APD group, the seizure outcome was also analyzed according to the types of APD (first and second generation APD and combination of first and second generation APD) and the types of psychiatric conditions (psychosis and non-psychosis). The seizure outcome was significantly better in the APD group than control group at all the four follow-up points. According to the epilepsy types, the improvement in the seizure outcome was only observed in the patients with partial epilepsy. Of the APD group, there was no significant difference in the seizure outcome according to the types of APD or the psychiatric conditions. In epilepsy patients who are already treated with AED, APD treatment seems safe in seizure control outcome for treatment of psychiatric conditions. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.
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Recent advances in very large area avalanche photodiodes
NASA Astrophysics Data System (ADS)
Squillante, Michael R.; Christian, James; Entine, Gerald; Farrell, Richard; Karger, Arieh M.; McClish, Mickel; Myers, Richard; Shah, Kanai S.; Taylor, David; Vanderpuye, Kofi; Waer, Peter; Woodring, Mitchell
2003-09-01
The Avalanche Photodiode (APD) is a unique device that combines the advantages of solid state photodetectors with those of high gain devices such as photomultiplier tubes (PMTs). APDs have internal gain that provides a high signal-to-noise ratio. APDs have high quantum efficiency, are fast, compact, and rugged. These properties make them suitable detectors for important applications such as LADAR, detection and identification toxic chemicals and bio-warfare agents, LIDAR fluorescence detection, stand-off laser induced breakdown spectroscopy (LIBS), and nuclear detectors and imagers. Recently there have been significant technical breakthroughs in fabricating very large APDs, APD arrays, and position sensitive APD arrays (PSAPD). Signal gain of over 10,000 has been achieved, single element APDs have been fabricated with active area greater than 40 cm2, monolithic pixelated arrays with up to 28 x 28 elements have been fabricated, and position sensitive APDs have been developed and tested. Additionally, significant progress has been made in improving the fabrication process to provide better uniformity and high yield, permitting cost effective manufacturing of APDs for reduced cost.
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Zhou, Xian-hui; Zhang, Jian; Gan, Tian-yi; Xu, Guo-jun; Tang, Bao-peng
2012-04-01
To investigate aging-related ionic remodeling of L-type voltage dependent calcium channel (LVDCC) in left atria of canine. Seven adult (2.0 - 2.5 years) and 10 aged (> 8 years) dogs were used. The current of LVDCC was recorded by patch clamp technique in the whole cell mode. The action potential duration (APD(90)), amplitude of action potential plateau (APA), I(Ca-L) peak current density of LVDCC were recorded. The mRNA and protein expressions of α1c subunit (Ca(V1.2)), sarcoplasmic reticulum Ca(2+)-ATPase (SECRA(2)), Calpain-I, ryanodine receptor (RYR(2)) were detected by quantitative RT-PCR and Western blot, respectively. I(Ca-L) peak current density [(-8.11 ± 0.54) pA/pF vs. (-14.04 ± 0.82) pA/pF, P < 0.05] was significantly reduced and action potential duration to 90% repolarization (APD(90)) significantly prolonged [(340.5 ± 10.1) ms vs. (320.0 ± 7.9) ms, P < 0.05] in aged group than in adult group. The mRNA gene expression level of Ca(V1.2) was significantly lower (0.90 ± 0.35 vs. 2.38 ± 0.40, P < 0.05) while mRNA expression of RYR(2) was significantly higher (4.39 ± 4.68 vs. 1.49 ± 1.69, P < 0.05) in the aged dogs than in the adult dogs. mRNA expression of SECRA(2) and Calpain-I was similar between the two groups. Similarly, the protein expression level of Ca(V1.2) was significantly lower (0.13 ± 0.10 vs. 0.29 ± 0.12, P < 0.05) while the protein expression level of RYR(2) was significantly higher (0.18 ± 0.21 vs. 0.08 ± 0.36, P < 0.05) in the aged dogs than in the adult dogs. Again, protein expression of SECRA(2), PLN(1) and Calpain-I was similar between the two groups. These data suggest that aging could induce mRNA and protein expression changes of Ca(V1.2) and RYR(2) of LVDCC which might serve as the molecular basis of I(Ca-L) remodeling in aged dogs and might be linked to the increased likelihood of developing atrial fibrillation (AF) in aged dogs.
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Toib, Amir; Zhang, Chen; Borghetti, Giulia; Zhang, Xiaoxiao; Wallner, Markus; Yang, Yijun; Troupes, Constantine D; Kubo, Hajime; Sharp, Thomas E; Feldsott, Eric; Berretta, Remus M; Zalavadia, Neil; Trappanese, Danielle M; Harper, Shavonn; Gross, Polina; Chen, Xiongwen; Mohsin, Sadia; Houser, Steven R
2017-09-01
Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases and among the leading causes of sudden cardiac death (SCD) in the young. The cellular mechanisms leading to SCD in HCM are not well known. Prolongation of the action potential (AP) duration (APD) is a common feature predisposing hypertrophied hearts to SCD. Previous studies have explored the roles of inward Na + and Ca 2+ in the development of HCM, but the role of repolarizing K + currents has not been defined. The objective of this study was to characterize the arrhythmogenic phenotype and cellular electrophysiological properties of mice with HCM, induced by myosin-binding protein C (MyBPC) knockout (KO), and to test the hypothesis that remodeling of repolarizing K + currents causes APD prolongation in MyBPC KO myocytes. We demonstrated that MyBPC KO mice developed severe hypertrophy and cardiac dysfunction compared with wild-type (WT) control mice. Telemetric electrocardiographic recordings of awake mice revealed prolongation of the corrected QT interval in the KO compared with WT control mice, with overt ventricular arrhythmias. Whole cell current- and voltage-clamp experiments comparing KO with WT mice demonstrated ventricular myocyte hypertrophy, AP prolongation, and decreased repolarizing K + currents. Quantitative RT-PCR analysis revealed decreased mRNA levels of several key K + channel subunits. In conclusion, decrease in repolarizing K + currents in MyBPC KO ventricular myocytes contributes to AP and corrected QT interval prolongation and could account for the arrhythmia susceptibility. NEW & NOTEWORTHY Ventricular myocytes isolated from the myosin-binding protein C knockout hypertrophic cardiomyopathy mouse model demonstrate decreased repolarizing K + currents and action potential and QT interval prolongation, linking cellular repolarization abnormalities with arrhythmia susceptibility and the risk for sudden cardiac death in hypertrophic cardiomyopathy. Copyright © 2017 the American Physiological Society.
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de Menezes-Filho, José Evaldo Rodrigues; Gondim, Antônio Nei Santana; Cruz, Jader Santos; de Souza, Américo Azevedo; Santos, José Nilson Andrade Dos; Conde-Garcia, Eduardo Antônio; de Sousa, Damião Pergentino; Santos, Michel Santana; de Oliveira, Evaleide Diniz; de Vasconcelos, Carla Maria Lins
2014-12-01
Geraniol is a monoterpene present in several essential oils, and it is known to have a plethora of pharmacological activities. In this study, we explored the contractile and electrophysiological properties of geraniol and its antiarrhythmic effects in the heart. The geraniol effects on atrial contractility, L-type Ca(2+) current, K(+) currents, action potential (AP) parameters, ECG profile and on the arrhythmia induced by ouabain were evaluated. In the atrium, geraniol reduced the contractile force (~98%, EC = 1,510 ± 160 μM) and diminished the positive inotropism of CaCl2 and BAY K8644. In cardiomyocytes, the IC a,L was reduced by 50.7% (n = 5) after perfusion with 300 μM geraniol. Moreover, geraniol prolonged the AP duration (APD) measured at 50% (n = 5) after repolarization, without changing the resting potential. The increased APD could be attributed to the blockade of the transient outward K(+) current (Ito ) (59.7%, n = 4), the non-inactivation K(+) current (Iss ) (39.2%, n = 4) and the inward rectifier K(+) current (IK 1 ) (33.7%, n = 4). In isolated hearts, geraniol increased PRi and QTi without affecting the QRS complex (n = 6), and it reduced both the left ventricular pressure (83%) and heart rate (16.5%). Geraniol delayed the time to onset of ouabain-induced arrhythmias by 128%, preventing 30% of the increase in resting tension (n = 6). Geraniol exerts its negative inotropic and chronotropic responses in the heart by decreasing both L-type Ca(2+) and voltage-gated K(+) currents, ultimately acting against ouabain-induced arrhythmias. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).
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Constant DI pacing suppresses cardiac alternans formation in numerical cable models
NASA Astrophysics Data System (ADS)
Zlochiver, S.; Johnson, C.; Tolkacheva, E. G.
2017-09-01
Cardiac repolarization alternans describe the sequential alternation of the action potential duration (APD) and can develop during rapid pacing. In the ventricles, such alternans may rapidly turn into life risking arrhythmias under conditions of spatial heterogeneity. Thus, suppression of alternans by artificial pacing protocols, or alternans control, has been the subject of numerous theoretical, numerical, and experimental studies. Yet, previous attempts that were inspired by chaos control theories were successful only for a short spatial extent (<2 cm) from the pacing electrode. Previously, we demonstrated in a single cell model that pacing with a constant diastolic interval (DI) can suppress the formation of alternans at high rates of activation. We attributed this effect to the elimination of feedback between the pacing cycle length and the last APD, effectively preventing restitution-dependent alternans from developing. Here, we extend this idea into cable models to study the extent by which constant DI pacing can control alternans during wave propagation conditions. Constant DI pacing was applied to ventricular cable models of up to 5 cm, using human kinetics. Our results show that constant DI pacing significantly shifts the onset of both cardiac alternans and conduction blocks to higher pacing rates in comparison to pacing with constant cycle length. We also demonstrate that constant DI pacing reduces the propensity of spatially discordant alternans, a precursor of wavebreaks. We finally found that the protective effect of constant DI pacing is stronger for increased electrotonic coupling along the fiber in the sense that the onset of alternans is further shifted to higher activation rates. Overall, these results support the potential clinical applicability of such type of pacing in improving protocols of implanted pacemakers, in order to reduce the risk of life-threatening arrhythmias. Future research should be conducted in order to experimentally validate these promising results.
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Central and Peripheral Mechanisms of Antipsychotic Medication Induced Metabolic Dysregulation
2016-10-01
consumption in hypothalamus-specific D2R (and wildtype littermate controls) treated with either with first-generation APD haloperidol or second-generation APD...wildtype littermate controls) treated with either with first-generation APD haloperidol or second-generation APD olanzapine (via i.p. administration
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Tang, Chao-Hsiun; Wu, Yu-Ting; Huang, Siao-Yuan; Chen, Hsi-Hsien; Wu, Ming-Ju; Hsu, Bang-Gee; Tsai, Jer-Chia; Chen, Tso-Hsiao; Sue, Yuh-Mou
2017-03-21
Taiwan succeeded in raising the proportion of peritoneal dialysis (PD) usage after the National Health Insurance (NHI) payment scheme introduced financial incentives in 2005. This study aims to compare the economic costs between automated PD (APD) and continuous ambulatory PD (CAPD) modalities from a societal perspective. A retrospective cohort of patients receiving PD from the NHI Research Database was identified during 2004-2011. The 1:1 propensity score matched 1749 APD patients and 1749 CAPD patients who were analysed on their NHI-financed medical costs and utilisation. A multicentre study by face-to-face interviews on 117 APD and 129 CAPD patients from five hospitals located in four regions of Taiwan was further carried out to collect data on their out-of-pocket payments, productivity losses and quality of life with EuroQol-5D-5L. The NHI-financed medical costs, out-of-pocket payments and productivity losses of APD and CAPD patients. The total NHI-financed medical costs per patient-year after 5 years of follow-up were significantly higher with APD than CAPD (US$23 005 vs US$19 237; p<0.01). In terms of dialysis-related costs, APD had higher costs resulting from the use of APD machines (US$795) and APD sets (US$2913). Significantly lower productivity losses were found with APD (US$2619) than CAPD (US$6443), but the out-of-pocket payments were not significantly different. The differences in NHI-financed medical costs and productivity losses between APD and CAPD remained robust in the bootstrap analysis. The total economic costs of APD (US$30 401) were similar to those of CAPD (US$29 939), even after bootstrap analysis (APD, US$28 399; CAPD, US$27 960). No discernable differences were found in the results of mortality and quality of life between the APD and CAPD patients. APD had higher annual dialysis-related costs and lower annual productivity losses than CAPD, which made the economic costs of APD very close to those of CAPD in Taiwan. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Gausia, Kaniz; Thompson, Sandra C; Nagel, Tricia; Schierhout, Gill; Matthews, Veronica; Bailie, Ross
2015-01-01
This study explored the risk of antenatal psychosocial distress (APD) and associated potential factors and examined management aspects of risk of APD in women attending Aboriginal primary health care services in Australia. Audits of medical records of 797 pregnant women from 36 primary health centres in five jurisdictions (NSW, QLD, SA, WA and NT) were undertaken as part of a quality improvement programme. Information collected included mental health assessed by a standard screening tools, enquiry regarding social and emotional well-being (SEWB), depression management (including antidepressant medications) and referral. Around 18% (n=141) of women were at risk of APD based on assessment using a standard screening tool or by SEWB enquiry. There was a significant association between risk of distress and women's life style behaviours (e.g., alcohol, illicit drug use) and health centre characteristics. Of the 141 women, 16% (n= 22) were prescribed antidepressant drugs during pregnancy. A range of nonpharmaceutical mental health interventions were also recorded, including brief intervention of 61% (n=86), counselling of 57% (n=80) and cognitive behaviour therapy of 5% (n=7). About 39% (n=55) of women with APD were referred to external services for consultations with a psychiatrist, psychologist or social worker or to a women's refuge centre. The higher risk of APD associated with women's life style behaviour indicates that the better understanding of mental health in its cultural context is essential. Copyright © 2015 Elsevier Inc. All rights reserved.
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1994-12-02
S94-47810 (2 Dec. 1994) --- Lockheed Space Operations Company workers in the Extended Duration Orbiter (EDO) Facility, located inside the Vehicle Assembly Building (VAB), carefully hoist the Orbiter Docking System (ODS) from its shipping container into a test stand. The ODS was shipped in a horizontal position to the Kennedy Space Center (KSC) from contractor Rockwell Aerospace's Downey plant. Once the ODS is upright, work can continue to prepare the hardware for the first docking of the United States Space Shuttle and Russian Space Station MIR in 1995. The ODS contains both United States-made and Russian-made hardware. The black band is Russian-made thermal insulation protecting part of the docking mechanism, also Russian-made, called the Androgynous Peripheral Docking System (APDS). A red protective cap covers the APDS itself. Other elements of the ODS, most of it protected by white United States-made thermal insulation, were developed by Rockwell, which also integrated and checked out the assembled Russian-United States system.
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Fossa, Anthony A
2017-09-01
Cardiac restitution is the ability of the heart to recover from one beat to the next. Ventricular arrhythmia vulnerability can occur when the heart does not properly adjust to sudden changes in rate or in hemodynamics leading to excessive temporal and/or spatial heterogeneity in conduction or repolarization. Restitution has historically been used to study, by invasive means, the dynamics of the relationship between action potential duration (APD) and diastolic interval (DI) in sedated subjects using various pacing protocols. Even though the analogous measures of APD and DI can be obtained using the surface ECG to acquire the respective QT and TQ intervals for ECG restitution, this methodology has not been widely adopted for a number of reasons. Recent development of more advanced software algorithms enables ECG intervals to be measured accurately, on a continuous beat-to-beat basis, in an automated manner, and under highly dynamic conditions (i.e., ambulatory or exercise) providing information beyond that available in the typical resting state. Current breakthroughs in ECG technology will allow ECG restitution measures to become a practical approach for providing quantitative measures of the risks for ventricular arrhythmias as well as cardiac stress in general. In addition to a review of the underlying principles and caveats of ECG restitution, a new approach toward an advancement of more integrated restitution biomarkers is proposed. © 2017 Wiley Periodicals, Inc.
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Abbasi, Mitra; Small, Ben G; Patel, Nikunjkumar; Jamei, Masoud; Polak, Sebastian
2017-02-01
To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects. To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models. This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)). We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.
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III-V strain layer superlattice based band engineered avalanche photodiodes (Presentation Recording)
NASA Astrophysics Data System (ADS)
Ghosh, Sid
2015-08-01
Laser detection and ranging (LADAR)-based systems operating in the Near Infrared (NIR) and Short Wave Infrared (SWIR) have become popular optical sensors for remote sensing, medical, and environmental applications. Sophisticated laser-based radar and weapon systems used for long-range military and astronomical applications need to detect, recognize, and track a variety of targets under a wide spectrum of atmospheric conditions. Infrared APDs play an important role in LADAR systems by integrating the detection and gain stages in a single device. Robust silicon-APDs are limited to visible and very near infrared region (< 1 um), while InGaAs works well up to wavelengths of about 1.5um. Si APDs have low multiplication or excess noise but are limited to below 1um due very poor quantum efficiency above 0.8um. InGaAs and Ge APDs operate up to wavelengths of 1.5um but have poor multiplication or excess noise due to a low impact ionization coefficient ratio between electrons and holes. For the past several decades HgCdTe has been traditionally used in longer wavelength (> 3um) infrared photon detection applications. Recently, various research groups (including Ghosh et. al.) have reported SWIR and MWIR HgCdTe APDs on CdZnTe and Si substrates. However, HgCdTe APDs suffer from low breakdown fields due to material defects, and excess noise increases significantly at high electric fields. During the past decade, InAs/GaSb Strain Layer Superlattice (SLS) material system has emerged as a potential material for the entire infrared spectrum because of relatively easier growth, comparable absorption coefficients, lower tunneling currents and longer Auger lifetimes resulting in enhanced detectivities (D*). Band engineering in type II SLS allows us to engineer avalanche properties of electrons and holes. This is a great advantage over bulk InGaAs and HgCdTe APDs where engineering avalanche properties is not possible. The talk will discuss the evolution of superlattice based avalanche photodiodes and some of the recent results on the work being done at Raytheon on SWIR avalanche photodiodes.
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Steć, Anna; Paluch-Oleś, Jolanta; Korolczuk, Agnieszka; Magdalena Grzebalska, Agnieszka; Kozioł-Montewka, Maria; Książek, Andrzej
Acquired perforating dermatosis (APD) represents a heterogenous group of skin disorders characterized histopathologically by transepithelial elimination (TEE) of dermal structures. APD is manifested clinically as multi-localized, papulo-nodular skin lesions accompanied by a refractory pruritus. APD typically coexists with long-term disorders, most often diabetic kidney disease (DKD). The paper presents a case of a 56-year-old male patient with chronic kidney disease (CKD) and concomitant acquired reactive perforating collagenosis (ARPC), which is a subtype of APD. Etiological theories of ARPC as well as current diagnostic and treatment principles in dermatosis were described. On the basis of the presented case report and the literature review attention was paid to diagnostic difficulties associated with APD. The assumption was made that APD can be an underdiagnosed disease and thus it is not treated correctly. According to the authors’ opinion, this is an important circumstance to popularize the knowledge about APD.
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NASA Astrophysics Data System (ADS)
Khidirov, I.
2015-09-01
The kinetics of formation and growth of ordered antiphase domains (APDs) in titanium carbohydride TiC0.50H0.21 has been investigated by neutron diffraction. A model of ordered APDs is proposed. It is established that the pronounced ordering of interstitial atoms and APDs begin at 450°C. It is shown that the period of ordered APDs ( Р ≈ 10-12) is independent of the exposure time at a constant temperature. It is found that the temperature of ordered APDs, T OAPD, increases nonlinearly with an increase in the carbon concentration in the range 0.50 ≤ C/Ti ≤ 0.70. The formation temperature of ordered APDs is found to correlate with the concentration dependence of the order-disorder transition temperature and be 0.60 of the order-disorder transition temperature: T APD = 0.60 Т С.
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Assessing Auditory Processing Abilities in Typically Developing School-Aged Children.
McDermott, Erin E; Smart, Jennifer L; Boiano, Julie A; Bragg, Lisa E; Colon, Tiffany N; Hanson, Elizabeth M; Emanuel, Diana C; Kelly, Andrea S
2016-02-01
Large discrepancies exist in the literature regarding definition, diagnostic criteria, and appropriate assessment for auditory processing disorder (APD). Therefore, a battery of tests with normative data is needed. The purpose of this study is to collect normative data on a variety of tests for APD on children aged 7-12 yr, and to examine effects of outside factors on test performance. Children aged 7-12 yr with normal hearing, speech and language abilities, cognition, and attention were recruited for participation in this normative data collection. One hundred and forty-seven children were recruited using flyers and word of mouth. Of the participants recruited, 137 children qualified for the study. Participants attended schools located in areas that varied in terms of socioeconomic status, and resided in six different states. Audiological testing included a hearing screening (15 dB HL from 250 to 8000 Hz), word recognition testing, tympanometry, ipsilateral and contralateral reflexes, and transient-evoked otoacoustic emissions. The language, nonverbal IQ, phonological processing, and attention skills of each participant were screened using the Clinical Evaluation of Language Fundamentals-4 Screener, Test of Nonverbal Intelligence, Comprehensive Test of Phonological Processing, and Integrated Visual and Auditory-Continuous Performance Test, respectively. The behavioral APD battery included the following tests: Dichotic Digits Test, Frequency Pattern Test, Duration Pattern Test, Random Gap Detection Test, Compressed and Reverberated Words Test, Auditory Figure Ground (signal-to-noise ratio of +8 and +0), and Listening in Spatialized Noise-Sentences Test. Mean scores and standard deviations of each test were calculated, and analysis of variance tests were used to determine effects of factors such as gender, handedness, and birth history on each test. Normative data tables for the test battery were created for the following age groups: 7- and 8-yr-olds (n = 49), 9- and 10-yr-olds (n = 40), and 11- and 12-yr-olds (n = 48). No significant effects were seen for gender or handedness on any of the measures. The data collected in this study are appropriate for use in clinical diagnosis of APD. Use of a low-linguistically loaded core battery with the addition of more language-based tests, when language abilities are known, can provide a well-rounded picture of a child's auditory processing abilities. Screening for language, phonological processing, attention, and cognitive level can provide more information regarding a diagnosis of APD, determine appropriateness of the test battery for the individual child, and may assist with making recommendations or referrals. It is important to use a multidisciplinary approach in the diagnosis and treatment of APD due to the high likelihood of comorbidity with other language, learning, or attention deficits. Although children with other diagnoses may be tested for APD, it is important to establish previously made diagnoses before testing to aid in appropriate test selection and recommendations. American Academy of Audiology.
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Nutritional Knowledge and Attitudes in Athletes With Physical Disabilities
Rastmanesh, Reza; Taleban, Furugh Azam; Kimiagar, Masood; Mehrabi, Yadolah; Salehi, Moosa
2007-01-01
Context: Little is known about sport nutritional problems and requirements of athletes with physical disabilities. Objective: To compare the nutritional knowledge and attitudes of Iranian athletes with physical disabilities (APDs) after nutrition education. Because proper nutrition is important for both performance and injury healing, learning about the nutritional areas in which APDs are deficient may assist professionals in educating them. Design: Nested case-control study. Setting: Sport camp. Patients or Other Participants: Seventy-two APDs (42 APDs in the intervention group and 30 age-matched and sex-matched control APDs) and 10 coaches completed the study. Intervention(s): The APDs in the intervention group and their coaches were given nutrition education, which included a booklet with a simplified food guide pyramid, simple concepts about nutrition and weight loss, and four 3-hour courses. The APDs in the control group and their coaches were not given nutrition education. Main Outcome Measure(s): Subjects completed 2 nutritional questionnaires with both quantitative and qualitative components. Nutritional questionnaires were administered at 2 consecutive camps, 30 days apart, before and after nutrition education. Our questionnaires included a demographics section; 88 Likert scale and true-false questions; and 18 open-ended questions, 13 of which were specifically designed for APDs. Each APD completed two 3-day food records. Results: The APDs in the intervention group scored significantly higher after nutrition education and higher than the control group on the knowledge subscales and interest in nutrition. Although the nutrition knowledge score in this study was moderate, several specific areas of deficient nutritional knowledge were identified that are critical for the health of APDs. Our model of nutrition education was more effective than the usual instructions presented irregularly by coaches. Conclusions: Our findings suggest that Iranian APDs lack nutritional knowledge in areas critical to preventing nutrition-related health problems, especially components related to nutrition for athletes with disabilities. PMID:17597950
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Vaidyanathan, Uma; Hall, Jason R.; Patrick, Christopher J.; Bernat, Edward M.
2010-01-01
Prior research has demonstrated deficits in defensive reactivity (indexed by potentiation of the startle blink reflex) in psychopathic individuals. However, the basis of this association remains unclear, as diagnostic criteria for psychopathy encompass two distinct phenotypic components that may reflect differing neurobiological mechanisms – an affective-interpersonal component, and an antisocial deviance component. Likewise, the role of defensive response deficits in antisocial personality disorder (APD), a related but distinct syndrome, remains to be clarified. The current study examined affective priming deficits in relation to factors of psychopathy and symptoms of APD using startle reflex methods in 108 adult male prisoners. Deficits in blink reflex potentiation during aversive picture viewing were found in relation to the affective-interpersonal (Factor 1) component of psychopathy, and to a lesser extent in relation to the antisocial deviance (Factor 2) component of psychopathy and symptoms of APD—but only as a function of their overlap with affective-interpersonal features of psychopathy. These findings provide clear evidence that deficits in defensive reactivity are linked specifically to the affective-interpersonal features of psychopathy, and not the antisocial deviance features represented most strongly in APD. PMID:20973594
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Liu, Wei-hui; Wang, Tao; Yan, Hong-tao; Chen, Tao; Xu, Chuan; Ye, Ping; Zhang, Ning; Liu, Zheng-cai; Tang, Li-jun
2015-01-01
Aims Although we previously demonstrated abdominal paracentesis drainage (APD) preceding percutaneous catheter drainage (PCD) as the central step for treating patients with moderately severe (MSAP) or severe acute pancreatitis (SAP), the predictors leading to PCD after APD have not been studied. Methods Consecutive patients with MSAP or SAP were recruited between June 2011 and June 2013. As a step-up approach, all patients initially received medical management, later underwent ultrasound-guided APD before PCD, if necessary, followed by endoscopic necrosectomy through the path formed by PCD. APD primarily targeted fluid in the abdominal or pelvic cavities, whereas PCD aimed at (peri)pancreatic fluid. Results Of the 92 enrolled patients, 40 were managed with APD alone and 52 received PCD after APD (14 required necrosectomy after initial PCD). The overall mortality was 6.5%. Univariate analysis showed that among the 20 selected parameters, 13 factors significantly affected PCD intervention after APD. Multivariate analysis revealed that infected (peri)pancreatic collections (P = -0.001), maximum extent of necrosis of more than 30% of the pancreas (P = -0.024), size of the largest necrotic peri(pancreatic) collection (P = -0.007), and reduction of (peri)pancreatic fluid collections by <50% after APD (P = -0.008) were all independent predictors of PCD. Conclusions Infected (peri)pancreatic collections, a largest necrotic peri(pancreatic) collection of more than 100 ml, and reduction of (peri)pancreatic fluid collections by <50% after APD could effectively predict the need for PCD in the early course of the disease. PMID:25659143
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Peritoneal dialysis technique success during the initial 90 days of therapy.
Guest, Steven; Hayes, Andrew C; Story, Kenneth; Davis, Ira D
2012-01-01
Comparisons of technique success by peritoneal dialysis (PD) modality have typically excluded the initial 90 days of therapy. We analyzed a database of 51,469 new PD starts from 2004 to 2008 in the United States. The analysis concentrated on the initial 90 days of therapy to determine technique success and the impact of the continuous ambulatory PD (CAPD) and automated PD (APD) modalities. Overall, 13.3% of patients stopped PD within 90 days. Of patients starting directly on APD, 14.3% stopped PD within 90 days. Of patients starting on CAPD, 12.6% stopped PD within 90 days, and 63.4% changed to APD within 90 days. Only 3.3% of the latter patients failed to reach 90 days of therapy. By comparison, technique failure occurred in 28.8% of those initiating with and remaining on CAPD. We conclude that initial training to perform CAPD, with timely transfer to APD within the first 3 months, was associated with the greatest technique success at 90 days. The reasons for that success are unclear, and further research should be directed to determining factors responsible. It is possible that patients trained initially to CAPD but converted to APD have a greater understanding of the total therapy, which improves confidence. Those converted to APD may be more appreciative of the lifestyle benefits of APD, which translates into improved compliance; alternatively, technical factors associated with APD may be responsible. Those technical factors may include improved catheter function in the recumbent position during APD or the reduced infection risk associated with just 2 connect/disconnect procedures in APD compared with 8 in CAPD.
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Evaluation of musical skills in children with a diagnosis of an auditory processing disorder.
Olakunbi, Deborah; Bamiou, Doris-Eva; Stewart, Lauren; Luxon, Linda M
2010-06-01
Impaired musical skills are reported in parental questionnaires to be present in children with an auditory processing disorder (APD). To formally assess musical skills in children with a diagnosis of APD. We used a validated musical test battery with extensive normative pediatric data, the Gordon's Musical Aptitude Profile and the tests of metre and melody in particular, in order to assess the musical skills of 8 children with a previously given diagnosis of APD (APD group) and 8 normal controls (control group) aged 7-15 years old. The two groups were well matched for age, sex, handedness, socio-economic factors and musical training. The APD group had significantly lower metre percentile scores than normal children (mean difference 28.9, p=0.003). Melody scores tended to be lower in the APD group than in the controls, but this did not reach significance, possibly due to low power of the study. This is the first study that systematically assesses musical skills in children with a formal diagnosis of APD in the absence of other developmental disorders. The APD group did significantly worse than the control group in judging metre. Musical skills assessment in children with APD may help constrain our understanding of this heterogeneous condition and possibly inform the management plan for these children. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.
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Use of active personal dosimeters in hospitals: EURADOS survey.
Ciraj-Bjelac, Olivera; Carinou, Eleftheria; Vanhavere, Filip
2018-06-01
Considering that occupational exposure in medicine is a matter of growing concern, active personal dosimeters (APDs) are also increasingly being used in different fields of application of ionising radiation in medicine. An extensive survey to collect relevant information regarding the use of APDs in medical imaging applications of ionising radiation was organised by the EURADOS (European Radiation Dosimetry Group) Working Group 12. The objective was to collect data about the use of APDs and to identify the basic problems in the use of APDs in hospitals. APDs are most frequently used in interventional radiology and cardiology departments (54%), in nuclear medicine (29%), and in radiotherapy (12%). Most types of APDs use silicon diodes as the detector; however, in many cases their calibration is not given proper attention, as radiation beam qualities in which they are calibrated differ significantly from those in which they are actually used. The survey revealed problems related to the use of APDs, including their reliability in pulsed x-ray fields that are widely used in hospitals. Guidance from regulatory authorities and professional organisations on the testing and calibration of APDs used in hospital would likely improve the situation.
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Progress in low light-level InAs detectors- towards Geiger-mode detection
NASA Astrophysics Data System (ADS)
Tan, Chee Hing; Ng, Jo Shien; Zhou, Xinxin; David, John; Zhang, Shiyong; Krysa, Andrey
2017-05-01
InAs avalanche photodiodes (APDs) can be designed such that only electrons are allowed to initiate impact ionization, leading to the lowest possible excess noise factor. Optimization of wet chemical etching and surface passivation produced mesa APDs with bulk dominated dark current and responsivity that are comparable and higher, respectively, than a commercial InAs detector. Our InAs electron-APDs also show high stability with fluctuation of 0.1% when operated at a gain of 11.2 over 60 s. These InAs APDs can detect very weak signal down to 35 photons per pulse. Fabrication of planar InAs by Be implantation produced planar APDs with bulk dominated dark current. Annealing at 550 °C was necessary to remove implantation damage and to activate Be dopants. Due to minimal diffusion of Be, thick depletion of 8 μm was achieved. Since the avalanche gain increases exponentially with the thickness of avalanche region, our planar APD achieved high gain > 300 at 200 K. Our work suggest that both mesa and planar InAs APDs can exhibit high gain. When combined with a suitable preamplifier, single photon detection using InAs electron-APDs could be achieved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Khidirov, I., E-mail: khidirov@inp.uz
2015-09-15
The kinetics of formation and growth of ordered antiphase domains (APDs) in titanium carbohydride TiC{sub 0.50}H{sub 0.21} has been investigated by neutron diffraction. A model of ordered APDs is proposed. It is established that the pronounced ordering of interstitial atoms and APDs begin at 450°C. It is shown that the period of ordered APDs (P ≈ 10–12) is independent of the exposure time at a constant temperature. It is found that the temperature of ordered APDs, T{sub OAPD}, increases nonlinearly with an increase in the carbon concentration in the range 0.50 ≤ C/Ti ≤ 0.70. The formation temperature of orderedmore » APDs is found to correlate with the concentration dependence of the order–disorder transition temperature and be 0.60 of the order–disorder transition temperature: T{sub APD} = 0.60Τ{sub C}.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Kim, Jin-Bae; Kim, Changsoo; Choi, Eunmi
2012-02-15
Ambient particulate matter (PM) can increase the incidence of arrhythmia. However, the arrhythmogenic mechanism of PM is poorly understood. This study investigated the arrhythmogenic mechanism of PM. In Sprague–Dawley rats, QT interval was increased from 115.0 ± 14.0 to 142.1 ± 18.4 ms (p = 0.02) after endotracheal exposure of DEP (200 μg/ml for 30 min, n = 5). Ventricular premature contractions were more frequently observed after DEP exposure (100%) than baseline (20%, p = 0.04). These effects were prevented by pretreatment of N-acetylcysteine (NAC, 5 mmol/L, n = 3). In 12 Langendorff-perfused rat hearts, DEP infusion of 12.5 μg/mlmore » for 20 min prolonged action potential duration (APD) at only left ventricular base increasing apicobasal repolarization gradients. Spontaneous early afterdepolarization (EAD) and ventricular tachycardia (VT) were observed in 8 (67%) and 6 (50%) hearts, respectively, versus no spontaneous triggered activity or VT in any hearts before DEP infusion. DEP-induced APD prolongation, EAD and VT were successfully prevented with NAC (5 mmol/L, n = 5), nifedipine (10 μmol/L, n = 5), and active Ca{sup 2+}/calmodulin-dependent protein kinase II (CaMKII) blockade, KN 93 (1 μmol/L, n = 5), but not by thapsigargin (200 nmol/L) plus ryanodine (10 μmol/L, n = 5) and inactive CaMKII blockade, KN 92 (1 μmol/L, n = 5). In neonatal rat cardiomyocytes, DEP provoked ROS generation in dose dependant manner. DEP (12.5 μg/ml) induced apoptosis, and this effect was prevented by NAC and KN 93. Thus, this study shows that in vivo and vitro exposure of PM induced APD prolongation, EAD and ventricular arrhythmia. These effects might be caused by oxidative stress and CaMKII activation. -- Highlights: ► The ambient PM consistently prolonged repolarization. ► The ambient PM induced triggered activity and ventricular arrhythmia. ► These effects were prevented by antioxidants, I{sub CaL} blockade and CaMKII blockade. ► The ambient PM can induce arrhythmia via oxidative stress and activation of CaMKII.« less
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Lee, Sujeong, E-mail: crystalee@gmail.com; Lee, Hyang-Ae, E-mail: hyangaelee@gmail.com; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799
2016-04-01
The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which express the major cardiac ion channels and recapitulate spontaneous mechanical and electrical activities, may provide a possible solution for the lack of in vitro human-based cardiotoxicity testing models. Cardiotoxicity induced by the antidepressant nefazodone was previously revealed to cause an acquired QT prolongation by hERG channel blockade. To elucidate the cellular mechanisms underlying the cardiotoxicity of nefazodone beyond hERG, its effects on cardiac action potentials (APs) and ion channels were investigated using hiPSC-CMs with whole-cell patch clamp techniques. In a proof of principle study, we examined the effectsmore » of cardioactive channel blockers on the electrophysiological profile of hiPSC-CMs in advance of the evaluation of nefazodone. Nefazodone dose-dependently prolonged the AP duration at 90% (APD{sub 90}) and 50% (APD{sub 50}) repolarization, reduced the maximum upstroke velocity (dV/dt{sub max}) and induced early after depolarizations. Voltage-clamp studies of hiPSC-CMs revealed that nefazodone inhibited various voltage-gated ion channel currents including I{sub Kr}, I{sub Ks}, I{sub Na}, and I{sub Ca}. Among them, I{sub Kr} and I{sub Na} showed relatively higher sensitivity to nefazodone, consistent with the changes in the AP parameters. In summary, hiPSC-CMs enabled an integrated approach to evaluate the complex interactions of nefazodone with cardiac ion channels. These results suggest that hiPSC-CMs can be an effective model for detecting drug-induced arrhythmogenicity beyond the current standard assay of heterologously expressed hERG K{sup +} channels. - Highlights: • Nefazodone prolonged APD and decreased upstroke velocity of APs in hiPSC-CMs. • Nefazodone inhibited cardiac ion channels, especially I{sub Kr} and I{sub Na}, in hiPSC-CMs. • Nefazodone-induced AP changes are mainly the result of I{sub Kr} and I{sub Na} inhibition. • hiPSC-CMs are sensitive model to validate nefazodone-induced cardiotoxicity. • hiPSC-CMs provide an integrated approach for evaluating mechanism of drug actions.« less
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Single Photon Counting Detectors for Low Light Level Imaging Applications
NASA Astrophysics Data System (ADS)
Kolb, Kimberly
2015-10-01
This dissertation presents the current state-of-the-art of semiconductor-based photon counting detector technologies. HgCdTe linear-mode avalanche photodiodes (LM-APDs), silicon Geiger-mode avalanche photodiodes (GM-APDs), and electron-multiplying CCDs (EMCCDs) are compared via their present and future performance in various astronomy applications. LM-APDs are studied in theory, based on work done at the University of Hawaii. EMCCDs are studied in theory and experimentally, with a device at NASA's Jet Propulsion Lab. The emphasis of the research is on GM-APD imaging arrays, developed at MIT Lincoln Laboratory and tested at the RIT Center for Detectors. The GM-APD research includes a theoretical analysis of SNR and various performance metrics, including dark count rate, afterpulsing, photon detection efficiency, and intrapixel sensitivity. The effects of radiation damage on the GM-APD were also characterized by introducing a cumulative dose of 50 krad(Si) via 60 MeV protons. Extensive development of Monte Carlo simulations and practical observation simulations was completed, including simulated astronomical imaging and adaptive optics wavefront sensing. Based on theoretical models and experimental testing, both the current state-of-the-art performance and projected future performance of each detector are compared for various applications. LM-APD performance is currently not competitive with other photon counting technologies, and are left out of the application-based comparisons. In the current state-of-the-art, EMCCDs in photon counting mode out-perform GM-APDs for long exposure scenarios, though GM-APDs are better for short exposure scenarios (fast readout) due to clock-induced-charge (CIC) in EMCCDs. In the long term, small improvements in GM-APD dark current will make them superior in both long and short exposure scenarios for extremely low flux. The efficiency of GM-APDs will likely always be less than EMCCDs, however, which is particularly disadvantageous for moderate to high flux rates where dark noise and CIC are insignificant noise sources. Research into decreasing the dark count rate of GM-APDs will lead to development of imaging arrays that are competitive for low light level imaging and spectroscopy applications in the near future.
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Performances of a HGCDTE APD based direct detection lidar at 2 μm. Application to dial measurements
NASA Astrophysics Data System (ADS)
Gibert, Fabien; Dumas, Arnaud; Rothman, Johan; Edouart, Dimitri; Cénac, Claire; Pellegrino, Jessica
2018-04-01
A lidar receiver with a direct detection chain adapted to a HgCdTe APD based detector with electric cooling is associated to a 2.05 μm Ho :YLF pulsed dual wavelength single mode transmitter to provide the first atmospheric lidar measurements using this technology. Experiments confirm the outstanding sensitivity of the detector and hightligth its huge potential for DIAL measurements of trace gas (CO2 and H2O) in this spectral domain. Performances of coherent vs direct detection at 2.05 μm is assessed.
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Cortés-Sanabria, Laura; Paredes-Ceseña, Carlos A; Herrera-Llamas, Rebeca M; Cruz-Bueno, Yolanda; Soto-Molina, Herman; Pazarín, Leonardo; Cortés, Margarita; Martínez-Ramírez, Héctor R
2013-11-01
The use of automated peritoneal dialysis (APD) is increasing compared to continuous ambulatory peritoneal dialysis (CAPD). Surprisingly, little data about health benefits and cost of APD exist, and virtually no information comparing the cost-utility between CAPD and APD is available. We undertook this study to evaluate and compare the health-related quality of life (HRQOL) and cost-utility indexes in patients on CAPD vs. This was a prospective cohort of patients initiating dialysis (2008-2009). Two questionnaires were self-administered: European Research Questionnaire Quality of Life (EQ-5D) and Kidney Disease Quality of Life (short form, KDQOL-SF, Rand, Santa Monica, CA). Direct medical costs (DMC) were determined from the health provider perspective including the following medical resource utilization: outpatient clinic/emergency care, dialysis procedures, medications, laboratory tests, hospitalization, and surgery. Cost-utility indexes were calculated dividing total mean cost by indicators of the HRQOL. One hundred twenty-three patients were evaluated: 77 on CAPD and 46 on APD. Results of the EQ-5D and KDQOL-SF questionnaires were significantly better in APD compared to the CAPD group. Main costs in both APD and CAPD were attributed to hospitalization and dialysis procedures followed by medication and surgery. Outpatient clinic visits and laboratory tests were significantly more costly in CAPD than in APD, whereas dialysis procedures were more expensive in the latter. Cost-utility indexes were significantly better in APD compared to CAPD. A significant cost-utility advantage of APD vs. CAPD was observed. The annual DMC per-patient were not different between groups but the HRQOL was better in the APD compared to the CAPD group. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.
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APD Response Time Measurements for Future TOF-E Systems
NASA Astrophysics Data System (ADS)
Starkey, M. J.; Ogasawara, K.; Dayeh, M. A.; Desai, M. I.
2017-12-01
In space physics, the ability to detect ions is crucial to understanding plasma distributions in the solar wind. This usually typically requires the determination of the particle's mass, charge, and total energy. Current ion detection schemes are implemented in three sequential parts; an electrostatic analyzer for energy per charge (E/Q) measurements, a time-of-flight (TOF) for mass per charge (M/Q) measurements, and a solid-state detector (SSD) for total energy (E) measurements. Recent work has suggested the use of avalanche photodiode detectors (APD) for a simultaneous TOF and total energy (TOF-E) measurement system, which would replace traditional SSDs, simplify design, and reduce costs. Although TOF based ion spectrometry typically requires timing resolution of <1ns, the timing profile for ion detection by APDs is not well understood. In this study we examine the timing profile of 3 different APDs for ion measurements over a suprathermal energy range of 50-300 keV. The three APDs differ by their doping type (N or P) and their detector thickness (30 μm or 150 μm). We find that APD P30, which is P doped and 30μm thick, provides the fastest rise times of the three APDs. Furthermore, these rise times are species independent and less than 1 ns. Our study shows that APDs are capable of sub-nanosecond response times for low energy ions and thus supports the future use of APDs in replacing SSDs in some TOF-E systems.
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The alkaloid matrine of the root of Sophora flavescens prevents arrhythmogenic effect of ouabain.
Zhou, Yuhong; Wu, Yun; Deng, Lin; Chen, Lanlan; Zhao, Dandan; Lv, Lifang; Chen, Xu; Man, Jinyu; Wang, Yansong; Shan, Hongli; Lu, Yanjie
2014-06-15
Matrine, a alkaloid of the root of Sophora flavescens, has multiple protective effects on the cardiovascular system including cardiac arrhythmias. However, the molecular and ionic mechanisms of matrine have not been well investigated. Our study aimed at to shed a light on the issue to investigate the antiarrhythmic effects of matrine by using ouabain to construct an arrhythmic model of cardiomyocytes. In this experiment, matrine significantly and dose-dependently increased the doses of ouabain required to induce cardiac arrhythmias and decreased the duration of arrhythmias in guinea pigs. In cardiomyocytes of guinea pigs, ouabain 10 μM prolonged action potential duration by 80% (p<0.05) and increased L-type Ca(2+) currents and Ca(2+) transients induced by KCl (p<0.05). Matrine 100 μM shortened the prolongation of APD and prevented the increase of L-type Ca(2+) currents and Ca(2+) transients induced by ouabain. Taken together, these findings provide the first evidence that matrine possessed arrhythmogenic effect of ouabain by inhibiting of L-type Ca(2+) currents and Ca(2+) overload in guinea pigs. Copyright © 2014 Elsevier GmbH. All rights reserved.
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Central and Peripheral Mechanisms of Antipsychotic Medication-Induced Metabolic Dysregulation
2016-10-01
generation APD haloperidol or second-generation APD olanzapine (via i.p. administration). We will also measure serum fasting glucose and insulin levels...food consumption in beta cell-specific D2R (and wildtype littermate controls) treated with either with first- generation APD haloperidol or second...effects of D2R agonists (dopamine, quinpirole) versus APD antagonists ( haloperidol and olanzapine). § We will treat pancreatic islets from wildtype
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APD in the developing world: is there a future?
Correa-Rotter, Ricardo
2002-01-01
Automated peritoneal dialysis (APD) has experienced significant growth in highly developed nations in the last few years, while in developing countries with important social, educational, and financial constraints this treatment modality is, at best, trying to emerge. APD offers advantages that make it popular. Some of these advantages include increased adequacy for some patient groups, enhanced patient well-being and positive changes in lifestyle, as well as a reduction in peritonitis rates attributed to fewer connect-disconnect procedures. The development of APD in developing nations has been very poor mainly due to educational and financial constraints. APD growth as a treatment modality in the developing world requires multiple approaches, some of them general and others related to the specific needs of each nation. There is a need to develop APD research projects and pilot programs to demonstrate the benefits for specific subpopulations. In addition, the development of research and industry-market strategies directed at reducing costs related to this form of treatment are required. The relatively low use of APD in developing nations is primarily influenced by nonmedical factors. Given the financial and educational constraints, APD programs may need to be directed toward specific subpopulations such as young working adults, individuals who require assistance to perform procedures, or patients who require an increased dialysis dose in order to reach adequate clearances.
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Jiang, Weixiong; Wang, Wei
2014-01-01
Antisocial Personality Disorder (APD) is a personality disorder that is most commonly associated with the legal and criminal justice systems. The study of the brain in APD has important implications in legal contexts and in helping ensure social stability. However, the neural contribution to the high prevalence of APD is still unclear. In this study, we used resting-state functional magnetic resonance imaging (fMRI) to investigate the underlying neural mechanisms of APD. Thirty-two healthy individuals and thirty-five patients with APD were recruited. The amplitude of low-frequency fluctuations (ALFF) was analyzed for the whole brain of all subjects. Our results showed that APD patients had a significant reduction in the ALFF in the right orbitofrontal cortex, the left temporal pole, the right inferior temporal gyrus, and the left cerebellum posterior lobe compared to normal controls. We observed that the right orbitofrontal cortex had a negative correlation between ALFF values and MMPI psychopathic deviate scores. Alterations in ALFF in these specific brain regions suggest that APD patients may be associated with abnormal activities in the fronto-temporal network. We propose that our results may contribute in a clinical and forensic context to a better understanding of APD. PMID:24598769
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Richard, Gail J
2011-07-01
A summary of issues regarding auditory processing disorder (APD) is presented, including some of the remaining questions and challenges raised by the articles included in the clinical forum. Evolution of APD as a diagnostic entity within audiology and speech-language pathology is reviewed. A summary of treatment efficacy results and issues is provided, as well as the continuing dilemma for speech-language pathologists (SLPs) charged with providing treatment for referred APD clients. The role of the SLP in diagnosing and treating APD remains under discussion, despite lack of efficacy data supporting auditory intervention and questions regarding the clinical relevance and validity of APD.
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Effects of premature stimulation on HERG K+ channels
Lu, Yu; Mahaut-Smith, Martyn P; Varghese, Anthony; Huang, Christopher L-H; Kemp, Paul R; Vandenberg, Jamie I
2001-01-01
The unusual kinetics of human ether-à-go-go-related gene (HERG) K+ channels are consistent with a role in the suppression of arrhythmias initiated by premature beats. Action potential clamp protocols were used to investigate the effect of premature stimulation on HERG K+ channels, transfected in Chinese hamster ovary cells, at 37 °C. HERG K+ channel currents peaked during the terminal repolarization phase of normally paced action potential waveforms. However, the magnitude of the current and the time point at which conductance was maximal depended on the type of action potential waveform used (epicardial, endocardial, Purkinje fibre or atrial). HERG K+ channel currents recorded during premature action potentials consisted of an early transient outward current followed by a sustained outward current. The magnitude of the transient current component showed a biphasic dependence on the coupling interval between the normally paced and premature action potentials and was maximal at a coupling interval equivalent to 90% repolarization (APD90) for ventricular action potentials. The largest transient current response occurred at shorter coupling intervals for Purkinje fibre (APD90– 20 ms) and atrial (APD90– 30 ms) action potentials. The magnitude of the sustained current response following premature stimulation was similar to that recorded during the first action potential for ventricular action potential waveforms. However, for Purkinje and atrial action potentials the sustained current response was significantly larger during the premature action potential than during the normally paced action potential. A Markov model that included three closed states, one open and one inactivated state with transitions permitted between the pre-open closed state and the inactivated state, successfully reproduced our results for the effects of premature stimuli, both during square pulse and action potential clamp waveforms. These properties of HERG K+ channels may help to suppress arrhythmias initiated by early afterdepolarizations and premature beats in the ventricles, Purkinje fibres or atria. PMID:11744759
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Avalanche photodiode photon counting receivers for space-borne lidars
NASA Technical Reports Server (NTRS)
Sun, Xiaoli; Davidson, Frederic M.
1991-01-01
Avalanche photodiodes (APD) are studied for uses as photon counting detectors in spaceborne lidars. Non-breakdown APD photon counters, in which the APD's are biased below the breakdown point, are shown to outperform: (1) conventional APD photon counters biased above the breakdown point; (2) conventional APD photon counters biased above the breakdown point; and (3) APD's in analog mode when the received optical signal is extremely weak. Non-breakdown APD photon counters were shown experimentally to achieve an effective photon counting quantum efficiency of 5.0 percent at lambda = 820 nm with a dead time of 15 ns and a dark count rate of 7000/s which agreed with the theoretically predicted values. The interarrival times of the counts followed an exponential distribution and the counting statistics appeared to follow a Poisson distribution with no after pulsing. It is predicted that the effective photon counting quantum efficiency can be improved to 18.7 percent at lambda = 820 nm and 1.46 percent at lambda = 1060 nm with a dead time of a few nanoseconds by using more advanced commercially available electronic components.
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Yalçinkaya, Fulya; Muluk, Nuray Bayar; Sahin, Semra
2009-08-01
The aim of this study was to investigate the effects of listening ability on speaking, writing and reading skills of children who was suspected of auditory processing difficulty (APD). This research was conducted with 67 children in 1st or 2nd grade of primary school. The first group (Group I-control) was comprised of 41 children without APD. The second group (Group II-study group) was comprised of 26 children with APD. Listening, speaking, reading and writing skills were evaluated by Observational Rating Scale (ORS) and analyzed in both groups. Listening value of ORS in APD group was significantly lower; and, speaking, reading and writing values of ORS in APD group were significantly higher than control group (p=0.000). It was also found that, the main effect of listening skills was on speaking in normal childs, and on writing ability in children with APD. It was concluded that, for school-aged children, APD can lead to or is associated with difficulties in written language.
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Hrabcová, Dana; Pásek, Michal; Šimurda, Jiří; Christé, Georges
2013-12-13
We have developed a computer model of human cardiac ventricular myocyte (CVM), including t-tubular and cleft spaces with the aim of evaluating the impact of accumulation-depletion of ions in restricted extracellular spaces on transmembrane ion transport and ionic homeostasis in human CVM. The model was based on available data from human CVMs. Under steady state, the effect of ion concentration changes in extracellular spaces on [Ca2+]i-transient was explored as a function of critical fractions of ion transporters in t-tubular membrane (not documented for human CVM). Depletion of Ca2+ and accumulation of K+ occurring in extracellular spaces slightly affected the transmembrane Ca2+ flux, but not the action potential duration (APD90). The [Ca2+]i-transient was reduced (by 2%-9%), depending on the stimulation frequency, the rate of ion exchange between t-tubules and clefts and fractions of ion-transfer proteins in the t-tubular membrane. Under non-steady state, the responses of the model to changes of stimulation frequency were analyzed. A sudden increase of frequency (1-2.5 Hz) caused a temporal decrease of [Ca2+] in both extracellular spaces, a reduction of [Ca2+]i-transient (by 15%) and APD90 (by 13 ms). The results reveal different effects of activity-related ion concentration changes in human cardiac t-tubules (steady-state effects) and intercellular clefts (transient effects) in the modulation of membrane ion transport and Ca2+ turnover.
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Davey, P; Bryant, S; Hart, G
2001-01-01
Left ventricular hypertrophy predisposes to sudden cardiac death (SCD) and studies of human SCD suggest that the antecedent heart rate (HR) is usually < 100 beats min(-1). This is surprising in view of the known association between adrenergic receptor stimulation and SCD which by itself would suggest that it is more likely to occur from high rather than low HR. We therefore hypothesized that there may be electrical or mechanical abnormalities present in myocytes isolated from animals with left ventricular hypertrophy that predispose to SCD at low stimulation frequencies but which may not be present at high HR. Mild left ventricular hypertrophy was induced in guinea-pigs by infra-renal aortic banding. Electrical and mechanical properties of isolated myocytes were studied at different stimulation frequencies between 0.1 and 3 Hz. Action potential duration (APD) is prolonged in hypertrophy at stimulation frequencies < 1 Hz but not at faster rates. Contraction size, time-to-peak contraction (TTPC) and half-relaxation time are greatly enhanced in hypertrophy at all frequencies between 0.1 and 3 Hz. Electrical (50.3 +/- 5.2 ms in hypertrophy and 78.4 +/- 12.1 ms in control, P < 0.03) and mechanical (205 +/- 16 ms for hypertrophy and 266 +/- 24 ms for control cells, P < 0.03) restitution time constants are quicker in hypertrophy. The finding of APD prolongation at low but not at high frequencies is consistent with the finding that SCD arises from low and not high HR. This data supports the role of abnormal repolarization in SCD.
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Fusshöller, Andreas; Grabensee, Bernd; Plum, Jörg
2003-01-01
In terms of the integrity of the peritoneal membrane in peritoneal dialysis (PD), the peritoneal mesothelial cells play a pivotal role since its monolayer constitutes the first line of the peritoneal membrane. Cancer antigen 125 (CA 125) is released by peritoneal mesothelial cells and correlates with the mesothelial cell mass in PD. Since its effluent concentration is easy to determine in chronic PD patients, CA 125 serves as an in vivo marker of biocompatibility. We performed a cross-sectional study to investigate the relation between PD duration, peritoneal transport and the PD regimen (CAPD/CCPD) on effluent CA 125 concentration in 22 chronic PD patients. We compared long-term (>6 months) with short-term PD treatment, patients with high small solute transport properties (MTAC >11 ml/min, d/p ratio of creatinine >0.72) to patients with low small solute transport and CAPD with APD patients. A peritoneal equilibration test was performed with 1.36% glucose. Dialysate/plasma (D/P) ratio and mass transfer area coefficient (MTAC) of creatinine were calculated and the 4-hour effluent concentration of CA 125 was determined. CA 125 tended to be lower in the long-term PD patients and also in APD patients, but statistical significance was missing. Effluent CA 125 was significantly increased in patients with an MTAC of creatinine >11 ml/min (40.2 +/- 11.2 vs. 20.7 +/- 1.2 U/ml) and in patients with a d/p ratio of creatinine >0.72 (48.2 +/- 11.0 vs. 21.6 +/- 1.6 U/ml). CA 125 and the d/p ratio of creatinine were positively correlated (r = 0.68). The positive correlation of CA 125 with peritoneal small solute transport especially in the early phase of PD treatment indicates an initial correlation of the mesothelial cell mass with the peritoneal surface area. A direct relation between the CA 125 concentration and peritoneal transport is unlikely. In our study the CA 125 effluent concentration tended to be lower in long-term PD patients and also in APD patients, possibly indicating a cell depletory influence of the conventional PD fluid. Copyright 2003 S. Karger AG, Basel
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Antisocial Personality as a Neurodevelopmental Disorder.
Raine, Adrian
2018-05-07
Although antisocial personality disorder (APD) is one of the most researched personality disorders, it is still surprisingly resistant to treatment. This lack of clinical progress may be partly due to the failure to view APD as a neurodevelopmental disorder and to consider early interventions. After first defining what constitutes a neurodevelopmental disorder, this review evaluates the extent to which APD meets neurodevelopmental criteria, covering structural and functional brain imaging, neurocognition, genetics and epigenetics, neurochemistry, and early health risk factors. Prevention and intervention strategies for APD are then outlined, focusing on addressing early biological and health systems, followed by forensic and clinical implications. It is argued both that APD meets criteria for consideration as a neurodevelopmental disorder and that consideration should be given both to the possibility that early onset conduct disorder is neurodevelopmental in nature, and also to the inclusion of psychopathy as a specifier in future Diagnostic and Statistical Manual revisions of APD.
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Testing limits to airflow perturbation device (APD) measurements.
Lopresti, Erika R; Johnson, Arthur T; Koh, Frank C; Scott, William H; Jamshidi, Shaya; Silverman, Nischom K
2008-10-31
The Airflow Perturbation Device (APD) is a lightweight, portable device that can be used to measure total respiratory resistance as well as inhalation and exhalation resistances. There is a need to determine limits to the accuracy of APD measurements for different conditions likely to occur: leaks around the mouthpiece, use of an oronasal mask, and the addition of resistance in the respiratory system. Also, there is a need for resistance measurements in patients who are ventilated. Ten subjects between the ages of 18 and 35 were tested for each station in the experiment. The first station involved testing the effects of leaks of known sizes on APD measurements. The second station tested the use of an oronasal mask used in conjunction with the APD during nose and mouth breathing. The third station tested the effects of two different resistances added in series with the APD mouthpiece. The fourth station tested the usage of a flexible ventilator tube in conjunction with the APD. All leaks reduced APD resistance measurement values. Leaks represented by two 3.2 mm diameter tubes reduced measured resistance by about 10% (4.2 cmH2O.sec/L for control and 3.9 cm H2O.sec/L for the leak). This was not statistically significant. Larger leaks given by 4.8 and 6.4 mm tubes reduced measurements significantly (3.4 and 3.0 cm cmH2O.sec/L, respectively). Mouth resistance measured with a cardboard mouthpiece gave an APD measurement of 4.2 cm H2O.sec/L and mouth resistance measured with an oronasal mask was 4.5 cm H2O.sec/L; the two were not significantly different. Nose resistance measured with the oronasal mask was 7.6 cm H2O.sec/L. Adding airflow resistances of 1.12 and 2.10 cm H2O.sec/L to the breathing circuit between the mouth and APD yielded respiratory resistance values higher than the control by 0.7 and 2.0 cm H2O.sec/L. Although breathing through a 52 cm length of flexible ventilator tubing reduced the APD measurement from 4.0 cm H2O.sec/L for the control to 3.6 cm H2O.sec/L for the tube, the difference was not statistically significant. The APD can be adapted for use in ventilated, unconscious, and uncooperative patients with use of a ventilator tube and an oronasal mask without significantly affecting measurements. Adding a resistance in series with the APD mouthpiece has an additive effect on resistance measurements, and can be used for qualitative calibration. A leak size of at least the equivalent of two 3.2 mm diameter tubes can be tolerated without significantly affecting APD measurements.
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El-Reshaid, Wael; Al-Disawy, Hanan; Nassef, Hossameldeen; Alhelaly, Usama
2016-09-01
Peritonitis is a common complication in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD). In this retrospective study, peritonitis rates and patient survival of 180 patients on CAPD and 128 patients on APD were compared in the period from January 2005 to December 2014 at Al-Nafisi Center in Kuwait. All patients had prophylactic topical mupirocin at catheter exit site. Patients on CAPD had twin bag system with Y transfer set. The peritonitis rates were 1 in 29 months in CAPD and 1 in 38 months in APD (p < 0.05). Percentage of peritonitis free patients over 10-year period in CAPD and APD were 49 and 60%, respectively (p < 0.05). Time to develop peritonitis was 10.25 ± 3.1 months in CAPD compared to 16.1 ± 4 months in APD (p < 0.001). Relapse and recurrence rates were similar in both groups. Median patient survival in CAPD and APD groups with peritonitis was 13.1 ± 1 and 14 ± 1.4 months respectively (p = 0.3) whereas in peritonitis free patients it was 15 ± 1.4 months in CAPD and 23 ± 3.1 months in APD (p = 0.025). APD had lower incidence rate of peritonitis than CAPD. Patient survival was better in APD than CAPD in peritonitis free patients but was similar in patients who had peritonitis.
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Haasum, Ylva; Fastbom, Johan; Johnell, Kristina
2016-01-01
Many drugs increase the risk of falls in old age. Although persons with Parkinson's disease (PD) are at increased risk of experiencing falls and fractures, the use of fall-risk inducing drugs (FRIDs) in this population has not previously been investigated. The objective of this study was to investigate the burden of use of FRIDs in older persons treated with anti-Parkinson drugs (APD; used as a proxy for PD), compared to persons without APD. We analyzed individual data on age, sex, type of housing and drug use in 1 346 709 persons aged ≥ 65 years in the Swedish Prescribed Drug Register on the date of 30 September 2008. Main outcome measure was the use of FRIDs. FRIDs were used by 79% of persons with APD and 75% of persons without APD. Persons with APD were more likely to use ≥ 1 FRIDs compared to persons without APD (adjusted OR: 1.09; 95% CI: 1.06-1-12). The association was stronger for concomitant use of ≥ 5 FRIDS (adjusted OR: 1.49; 95% CI: 1.44-1.55). The high use of FRIDs among persons with APD indicates that these patients may be at increased risk of drug-induced falls. Further studies are needed to investigate how these drugs affect the risk of falling in persons with PD.
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Haasum, Ylva; Fastbom, Johan; Johnell, Kristina
2016-01-01
Objectives Many drugs increase the risk of falls in old age. Although persons with Parkinson’s disease (PD) are at increased risk of experiencing falls and fractures, the use of fall-risk inducing drugs (FRIDs) in this population has not previously been investigated. The objective of this study was to investigate the burden of use of FRIDs in older persons treated with anti-Parkinson drugs (APD; used as a proxy for PD), compared to persons without APD. Methods We analyzed individual data on age, sex, type of housing and drug use in 1 346 709 persons aged ≥ 65 years in the Swedish Prescribed Drug Register on the date of 30 September 2008. Main outcome measure was the use of FRIDs. Results FRIDs were used by 79% of persons with APD and 75% of persons without APD. Persons with APD were more likely to use ≥ 1 FRIDs compared to persons without APD (adjusted OR: 1.09; 95% CI: 1.06-1-12). The association was stronger for concomitant use of ≥ 5 FRIDS (adjusted OR: 1.49; 95% CI: 1.44–1.55). Conclusions The high use of FRIDs among persons with APD indicates that these patients may be at increased risk of drug-induced falls. Further studies are needed to investigate how these drugs affect the risk of falling in persons with PD. PMID:27537366
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Pan, J.; Saltos, A.; Smith, D.; Johnson, A.; Vossoughi, J.
2013-01-01
The airflow perturbation device (APD) has been developed as a portable, easy to use, and a rapid response instrument for measuring respiratory resistance in humans. However, the APD has limited data validating it against the established techniques. This study used a mechanical system to simulate the normal range of human breathing to validate the APD with the clinically accepted impulse oscillometry (IOS) technique. The validation system consisted of a sinusoidal flow generator with ten standardized resistance configurations that were shown to represent a total range of resistances from 0.12 to 0.95 kPa·L−1 ·s (1.2–9.7 cm H2O·L−1 ·s). Impulse oscillometry measurements and APD measurements of the mechanical system were recorded and compared at a constant airflow of 0.15 L·s−1. Both the IOS and APD measurments were accurate in assessing nominal resistance. In addition, a strong linear relationship was observed between APD measurements and IOS measurements (R 2 = 0.999). A second series of measurements was made on ten human volunteers with external resistors added in their respiratory flow paths. Once calibrated with the mechanical system, the APD gave respiratory resistance measurements within 5% of IOS measurements. Because of their comparability to IOS measurements, APD measurements are shown to be valid representations of respiratory resistance. PMID:27006908
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Pro‐arrhythmic atrial phenotypes in incrementally paced murine Pgc1β −/− hearts: effects of age
Valli, Haseeb; Ahmad, Shiraz; Fraser, James A.; Jeevaratnam, Kamalan
2017-01-01
New Findings What is the central question of this study? Can we experimentally replicate atrial pro‐arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age‐dependent atrial arrhythmic phenotypes in Langendorff‐perfused murine Pgc1β −/− hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro‐arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12–16 week) and aged (>52 week) wild‐type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)‐deficient (Pgc1β −/−) Langendorff‐perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole‐heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β −/− hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dt max) were reduced in Pgc1β −/− hearts. Action potential latencies were increased by the Pgc1β −/− genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD90) were shorter in Pgc1β −/− hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and Pgc1β −/− hearts. Limiting slopes of restitution curves of APD90 against diastolic interval were correspondingly reduced interactively by Pgc1β −/− genotype and age. In contrast, reduced AP wavelengths were associated with Pgc1β −/− genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged Pgc1β −/− hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here. PMID:28960529
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Hortigon-Vinagre, M P; Zamora, V; Burton, F L; Green, J; Gintant, G A; Smith, G L
2016-12-01
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and higher throughput platforms have emerged as potential tools to advance cardiac drug safety screening. This study evaluated the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM. Human iPSC-CM from 2 commercial sources (Cor.4U and iCell Cardiomyocytes) were stained with the VSD di-4-ANEPPS and placed in a specialized photometry system that simultaneously monitors 2 wavebands of emitted fluorescence, allowing ratiometric measurement of membrane voltage. Signals were acquired at 10 kHz and analyzed using custom software. Action potential duration (APD) values were normally distributed in cardiomyocytes (CMC) from both sources though the mean and variance differed significantly (APD 90 : 229 ± 15 ms vs 427 ± 49 ms [mean ± SD, P < 0.01]; average spontaneous cycle length: 0.99 ± 0.02 s vs 1.47 ± 0.35 s [mean ± SD, P < 0.01], Cor.4U vs iCell CMC, respectively). The 10-90% rise time of the AP (T rise ) was ∼6 ms and was normally distributed when expressed as 1/[Formula: see text] in both cell preparations. Both cell types showed a rate dependence analogous to that of adult human cardiac cells. Furthermore, nifedipine, ranolazine, and E4031 had similar effects on cardiomyocyte electrophysiology in both cell types. However, ranolazine and E4031 induced early after depolarization-like events and high intrinsic firing rates at lower concentrations in iCell CMC. These data show that VSDs provide a minimally invasive, quantitative, and accurate method to assess hiPSC-CM electrophysiology and detect subtle drug-induced effects for drug safety screening while highlighting a need to standardize experimental protocols across preparations. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology.
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Verona, Edelyn; Sprague, Jenessa; Sadeh, Naomi
2012-05-01
The field of personality disorders has had a long-standing interest in understanding interactions between emotion and inhibitory control, as well as neurophysiological indices of these processes. More work in particular is needed to clarify differential deficits in offenders with antisocial personality disorder (APD) who differ on psychopathic traits, as APD and psychopathy are considered separate, albeit related, syndromes. Evidence of distinct neurobiological processing in these disorders would have implications for etiology-based personality disorder taxonomies in future psychiatric classification systems. To inform this area of research, we recorded event-related brain potentials during an emotional-linguistic Go/No-Go task to examine modulation of negative emotional processing by inhibitory control in three groups: psychopathy (n = 14), APD (n = 16), and control (n = 15). In control offenders, inhibitory control demands (No-Go vs. Go) modulated frontal-P3 amplitude to negative emotional words, indicating appropriate prioritization of inhibition over emotional processing. In contrast, the psychopathic group showed blunted processing of negative emotional words regardless of inhibitory control demands, consistent with research on emotional deficits in psychopathy. Finally, the APD group demonstrated enhanced processing of negative emotion words in both Go and No-Go trials, suggesting a failure to modulate negative emotional processing when inhibitory control is required. Implications for emotion-cognition interactions and putative etiological processes in these personality disorders are discussed.
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Ralston, S H; Hacking, L; Willocks, L; Bruce, F; Pitkeathly, D A
1989-01-01
A placebo controlled, double blind study of aminohydroxypropylidene bisphosphonate (APD), given by monthly intravenous infusion, was conducted in 40 patients with rheumatoid arthritis. Biochemical markers of increased bone resorption, such as fasting urinary calcium/creatinine ratio and hydroxyproline/creatinine ratio, were suppressed significantly in the APD group to approximately 50% and 60% of the pretreatment level respectively, and serum calcium fell transiently after the first APD infusion. There was no significant effect on disease activity in either the APD or placebo groups as judged by clinical (grip strength, morning stiffness, visual analogue score) or laboratory (haemoglobin, platelet count, erythrocyte sedimentation rate, C reactive protein) criteria. An exception was the articular index which improved to a similar degree in both groups, falling from (mean (SEM] 13.8 (1.8) to 7.2 (2.2) in the APD group and from 13.7 (1.9) to 6.8 (1.5) in the placebo group. Radiological progression occurred to a similar degree in both groups as assessed by the Sharp index (mean (SEM) 86 (13.1) v 95 (12.9)-APD group; 103 (15.1) v 110 (15.8)-placebo group), but there was no significant change in the Larsen index in either group (mean (SEM) 53 (4.2) v 57 (3.8)-APD; 62 (5.8) v 63 (5.6)-placebo). The lack of effect on radiological progression in the APD group indicates that focal erosive disease may either have progressed as the result of a non-osteoclast related mechanism, or that the intensity of bone resorption was too great to be inhibited by the doses of APD used. The biochemical response to APD presumably reflected inhibition of bone resorption at other sites, suggesting that further studies of the effects of bisphosphates on periarticular and systemic osteoporosis in rheumatoid arthritis may be of the interest. PMID:2658875
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Diagnosis and subtypes of adolescent antisocial personality disorder.
Jones, Meredith; Westen, Drew
2010-04-01
The present study examined the application of the Antisocial Personality Disorder (APD) diagnosis to adolescents and investigated the possibility of subtypes of APD adolescents. As part of a broader study of adolescent personality in clinically-referred patients, experienced clinicians provided personality data on a randomly selected patient in their care using the SWAP-II-A personality pathology instrument. Three hundred thirteen adolescents met adult DSM-IV diagnostic criteria for APD. To characterize adolescents with the disorder, we aggregated the data to identify the items most descriptive and distinctive of APD adolescents relative to other teenagers in the sample (N = 950). Q-factor analysis identified five personality subtypes: psychopathic-like, socially withdrawn, impulsive-histrionic, emotionally dysregulated, and attentionally dysregulated. The five subtypes differed in predictable ways on a set of external criteria related to global adaptive functioning, childhood family environment, and family history of psychiatric illness. Both the APD diagnosis and the empirically derived APD subtypes provided incremental validity over and above the DSM-IV disruptive behavior disorders in predicting global adaptive functioning, number of arrests, early-onset severe externalizing pathology, and quality of peer relationships. Although preliminary, these results provide support for the use of both APD and personality-based subtyping systems in adolescents.
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Federal Register 2010, 2011, 2012, 2013, 2014
2011-07-15
... Checklist: Medicaid Eligibility & Enrollment Systems--Advance Planning Document (E&E-APD); Use: Under... Eligibility/Enrollment Systems APD approval assignment. The information requested on the Checklist will be... an Expedited Checklist: Medicaid Eligibility & Enrollment Systems--Advance Planning Document (E& -APD...
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Hirsch, Jan D; Oen, Austin; Robertson, Suzie; Nguyen, Nancy; Daniels, Charles
2009-01-01
To assess the rate of patient-requested pharmacist counseling for refill prescriptions and satisfaction with pick-up process for patients using an automated prescription delivery system (APDS) versus those using a regular pick-up counter and to explore patient willingness to use an APDS as a tool for pharmacist monitoring of medication therapy outcomes. In this uncontrolled, cross-sectional, survey study, we assessed use of APDS or the regular counter by 116 patients picking up refill prescriptions at two community pharmacies. The main outcome measures were number of patients requesting pharmacist counseling for refill prescriptions, patient satisfaction with pick-up process, and patient willingness to use an APDS to report medication therapy outcomes. None of the regular counter users and only two APDS users (3.7%) requested counseling for their refill prescription (P = 0.126). Almost all patients agreed that they were able to talk to a pharmacist about their prescription if they wanted to do so (95.1% regular counter and 92.3% APDS; P = 0.268). The majority (75%) of patients using APDS indicated that they would be willing to use the system to answer questions or perform simple tests to provide information that the pharmacist could use to improve medication effectiveness or reduce adverse effects. Very few patients (ADPS or regular counter) asked to speak to a pharmacist about their refill medications, although it appeared that no perceived barriers to pharmacist access existed. Most APDS patients were willing to use this new technology to provide information about therapy outcomes to the pharmacist. Further exploration and testing of the APDS as a data collection tool to enhance pharmacist access to therapy outcomes is warranted.
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Near-IR photon number resolving detector design
NASA Astrophysics Data System (ADS)
Bogdanski, Jan; Huntington, Elanor H.
2013-05-01
Photon-Number-Resolving-Detection (PNRD) capability is crucial for many Quantum-Information (QI) applications, e.g. for Coherent-State-Quantum-Computing, Linear-Optics-Quantum-Computing. In Quantum-Key-Distribution and Quantum-Secret-Sharing over 1310/1550 nm fiber, two other important, defense and information security related, QI applications, it's crucial for the information transmission security to guarantee that the information carriers (photons) are single. Thus a PNRD can provide an additional security level against eavesdropping. Currently, there are at least a couple of promising PNRD technologies in the Near-Infrared, but all of them require cryogenic cooling. Thus a compact, portable PNRD, based on commercial Avalanche-Photo-Diodes (APDs), could be a very useful instrument for many QI experiments. For an APD-based PNRD, it is crucial to measure the APD-current in the beginning of the avalanche. Thus an efficient cancellation of the APD capacitive spikes is a necessary condition for the very weak APD current measurement. The detector's principle is based on two commercial, pair-matched InGaAs/InP APDs, connected in series. It leads to a great cancelation of the capacitive spikes caused by the narrow (300 ps), differential gate-pulses of maximum 4V amplitude assuming that both pulses are perfectly matched in regards to their phases, amplitudes, and shapes. The cancellation scheme could be used for other APD-technologies, e.g. Silicon, extending the detection spectrum from visible to NIR. The design distinguishes itself from other, APD-based, schemes by its scalability feature and its computer controlled cancellation of the capacitive spikes. Furthermore, both APDs could be equally used for the detection purpose, which opens a possibility for the odd-even photon number parity detection.
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Maccari, Maria Elena; Abolhassani, Hassan; Aghamohammadi, Asghar; Aiuti, Alessandro; Aleinikova, Olga; Bangs, Catherine; Baris, Safa; Barzaghi, Federica; Baxendale, Helen; Buckland, Matthew; Burns, Siobhan O.; Cancrini, Caterina; Cant, Andrew; Cathébras, Pascal; Cavazzana, Marina; Chandra, Anita; Conti, Francesca; Coulter, Tanya; Devlin, Lisa A.; Edgar, J. David M.; Faust, Saul; Fischer, Alain; Garcia-Prat, Marina; Hammarström, Lennart; Heeg, Maximilian; Jolles, Stephen; Karakoc-Aydiner, Elif; Kindle, Gerhard; Kiykim, Ayca; Kumararatne, Dinakantha; Grimbacher, Bodo; Longhurst, Hilary; Mahlaoui, Nizar; Milota, Tomas; Moreira, Fernando; Moshous, Despina; Mukhina, Anna; Neth, Olaf; Neven, Benedicte; Nieters, Alexandra; Olbrich, Peter; Ozen, Ahmet; Schmid, Jana Pachlopnik; Picard, Capucine; Prader, Seraina; Rae, William; Reichenbach, Janine; Rusch, Stephan; Savic, Sinisa; Scarselli, Alessia; Scheible, Raphael; Sediva, Anna; Sharapova, Svetlana O.; Shcherbina, Anna; Slatter, Mary; Soler-Palacin, Pere; Stanislas, Aurelie; Suarez, Felipe; Tucci, Francesca; Uhlmann, Annette; van Montfrans, Joris; Warnatz, Klaus; Williams, Anthony Peter; Wood, Phil; Kracker, Sven; Condliffe, Alison Mary; Ehl, Stephan
2018-01-01
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies. PMID:29599784
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Maccari, Maria Elena; Abolhassani, Hassan; Aghamohammadi, Asghar; Aiuti, Alessandro; Aleinikova, Olga; Bangs, Catherine; Baris, Safa; Barzaghi, Federica; Baxendale, Helen; Buckland, Matthew; Burns, Siobhan O; Cancrini, Caterina; Cant, Andrew; Cathébras, Pascal; Cavazzana, Marina; Chandra, Anita; Conti, Francesca; Coulter, Tanya; Devlin, Lisa A; Edgar, J David M; Faust, Saul; Fischer, Alain; Garcia-Prat, Marina; Hammarström, Lennart; Heeg, Maximilian; Jolles, Stephen; Karakoc-Aydiner, Elif; Kindle, Gerhard; Kiykim, Ayca; Kumararatne, Dinakantha; Grimbacher, Bodo; Longhurst, Hilary; Mahlaoui, Nizar; Milota, Tomas; Moreira, Fernando; Moshous, Despina; Mukhina, Anna; Neth, Olaf; Neven, Benedicte; Nieters, Alexandra; Olbrich, Peter; Ozen, Ahmet; Schmid, Jana Pachlopnik; Picard, Capucine; Prader, Seraina; Rae, William; Reichenbach, Janine; Rusch, Stephan; Savic, Sinisa; Scarselli, Alessia; Scheible, Raphael; Sediva, Anna; Sharapova, Svetlana O; Shcherbina, Anna; Slatter, Mary; Soler-Palacin, Pere; Stanislas, Aurelie; Suarez, Felipe; Tucci, Francesca; Uhlmann, Annette; van Montfrans, Joris; Warnatz, Klaus; Williams, Anthony Peter; Wood, Phil; Kracker, Sven; Condliffe, Alison Mary; Ehl, Stephan
2018-01-01
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.
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Acquired perforating dermatosis: a report of 8 cases.
González-Lara, L; Gómez-Bernal, S; Vázquez-López, F; Vivanco-Allende, B
2014-01-01
Acquired perforating dermatosis (APD) is an uncommon disease characterized by lesions exhibiting transepidermal elimination of collagen or elastic fibers. APD affects adults and is associated with systemic diseases, mainly diabetes mellitus and renal failure. We present 8 cases of APD. Seven patients had concomitant diabetes mellitus with or without chronic renal failure, and 1 had alcoholic cirrhosis. In the patients with chronic renal failure, the onset of APD coincided with transient worsening of renal function. The mean increase in creatinine concentrations above baseline was 1.14mg/dL. Acute deterioration of renal function may be involved in APD. Further studies are needed to investigate this association. Copyright © 2013 Elsevier España, S.L. y AEDV. All rights reserved.
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Towards on-chip integration of brain imaging photodetectors using standard CMOS process.
Kamrani, Ehsan; Lesage, Frederic; Sawan, Mohamad
2013-01-01
The main effects of on-chip integration on the performance and efficiency of silicon avalanche photodiode (SiAPD) and photodetector front-end is addressed in this paper based on the simulation and fabrication experiments. Two different silicon APDs are fabricated separately and also integrated with a transimpedance amplifier (TIA) front-end using standard CMOS technology. SiAPDs are designed in p+/n-well structure with guard rings realized in different shapes. The TIA front-end has been designed using distributed-gain concept combined with resistive-feedback and common-gate topology to reach low-noise and high gain-bandwidth product (GBW) characteristics. The integrated SiAPDs show higher signal-to-noise ratio (SNR), sensitivity and detection efficiency comparing to the separate SiAPDs. The integration does not show a significant effect on the gain and preserves the low power consumption. Using APDs with p-well guard-ring is preferred due to the higher observed efficiency after integration.
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Integrated Vegetation Management Plan, Statewide M & O, Transportation &
select herbicides that minimize potential risks to human health and the environment. All herbicide (APDES) Pesticides General Permit. Additionally, regional setbacks may be established for applications
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Expected radiation damage of reverse-type APDs for the Astro-H mission
NASA Astrophysics Data System (ADS)
Kataoka, J.; Saito, T.; Yoshino, M.; Mizoma, H.; Nakamori, T.; Yatsu, Y.; Ishikawa, Y.; Matsunaga, Y.; Tajima, H.; Kokubun, M.; Edwards, P. G.
2012-06-01
Scheduled for launch in 2014, Astro-H is the sixth Japanese X-ray astronomy satellite mission. More than 60 silicon avalanche photodiodes (Si-APDs; hereafter APDs) will be used to read out BGO scintillators, which are implemented to generate a veto signal to reduce background contamination for the hard X-ray imager (HXI) and a soft gamma-ray detector (SGD). To date, however, APDs have rarely been used in space experiments. Moreover, strict environmental tests are necessary to guarantee APD performance for missions expected to extend beyond five years. The radiation hardness of APDs, as for most semiconductors, is particularly crucial, since radiation in the space environment is severe. In this paper, we present the results of radiation tests conducted on reverse-type APDs (provided by Hamamatsu Photonics) irradiated by gamma rays (60Co) and 150 MeV protons. We show that, even under the same 100 Gy dose, high energy protons can cause displacement (bulk) damage in the depletion region and possibly change the activation energy, whereas gamma-ray irradiation is less prone to cause damage, because ionization damage dominates only the surface region. We also present quantitative guidance on how to estimate APD noise deterioration over a range of temperatures and radiation doses. As a practical example, we discuss the expected degradation of the BGO energy threshold for the generation of veto signals, following several years of Astro-H operation in Low Earth Orbit (LEO), and directly compare it to experimental results obtained using a small BGO crystal.
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75 FR 66319 - State Systems Advance Planning Document (APD) Process
Federal Register 2010, 2011, 2012, 2013, 2014
2010-10-28
...) equipment and services. The APD process was designed to mitigate financial risks, avoid incompatibilities... develop a General Systems Design (GSD). Implementation APD means a recorded plan of action to request Federal financial participation (FFP) in the costs of designing, developing and implementing the system...
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Spectral dependence of the main parameters of ITE silicon avalanche photodiodes
NASA Astrophysics Data System (ADS)
Wegrzecka, Iwona; Grynglas, Maria; Wegrzecki, Maciej
2001-08-01
New applications for avalanche photodiodes (APDs) as in systems using visible radiation, have prompted the need for the evaluation of detection properties of ITE APDs in the 400 divided by 700 nm spectral range. The paper presents the method and result of studies on the spectral dependence of the gain, dark and noise currents, sensitivity and excess noise factor of ITE APDs. The studies have shown that ITE APDs optimized for the near IR radiation can be effectively applied in the detection of radiation above the 500 nm wavelength.
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Gain properties of doped GaAs/AlGaAs multiple quantum well avalanche photodiode structures
NASA Technical Reports Server (NTRS)
Menkara, H. M.; Wagner, B. K.; Summers, C. J.
1995-01-01
A comprehensive characterization has been made of the static and dynamical response of conventional and multiple quantum well (MQW) avalanche photodiodes (APDs). Comparison of the gain characteristics at low voltages between the MQW and conventional APDs show a direct experimental confirmation of a structure-induced carrier multiplication due to interband impact ionization. Similar studies of the bias dependence of the excess noise characteristics show that the low-voltage gain is primarily due to electron ionization in the MQW-APDS, and to both electron and hole ionization in the conventional APDS. For the doped MQW APDS, the average gain per stage was calculated by comparing gain data with carrier profile measurements, and was found to vary from 1.03 at low bias to 1.09 near avalanche breakdown.
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Multiple benefits of personal FM system use by children with auditory processing disorder (APD).
Johnston, Kristin N; John, Andrew B; Kreisman, Nicole V; Hall, James W; Crandell, Carl C
2009-01-01
Children with auditory processing disorders (APD) were fitted with Phonak EduLink FM devices for home and classroom use. Baseline measures of the children with APD, prior to FM use, documented significantly lower speech-perception scores, evidence of decreased academic performance, and psychosocial problems in comparison to an age- and gender-matched control group. Repeated measures during the school year demonstrated speech-perception improvement in noisy classroom environments as well as significant academic and psychosocial benefits. Compared with the control group, the children with APD showed greater speech-perception advantage with FM technology. Notably, after prolonged FM use, even unaided (no FM device) speech-perception performance was improved in the children with APD, suggesting the possibility of fundamentally enhanced auditory system function.
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High-performance fused indium gallium arsenide/silicon photodiode
NASA Astrophysics Data System (ADS)
Kang, Yimin
Modern long haul, high bit rate fiber-optic communication systems demand photodetectors with high sensitivity. Avalanche photodiodes (APDs) exhibit superior sensitivity performance than other types of photodetectors by virtual of its internal gain mechanism. This dissertation work further advances the APD performance by applying a novel materials integration technique. It is the first successful demonstration of wafer fused InGaAs/Si APDs with low dark current and low noise. APDs generally adopt separate absorption and multiplication (SAM) structure, which allows independent optimization of materials properties in two distinct regions. While the absorption material needs to have high absorption coefficient in the target wavelength range to achieve high quantum efficiency, it is desirable for the multiplication material to have large discrepancy between its electron and hole ionization coefficients to reduce noise. According to these criteria, InGaAs and Si are the ideal materials combination. Wafer fusion is the enabling technique that makes this theoretical ideal an experimental possibility. APDs fabricated on the fused InGaAs/Si wafer with mesa structure exhibit low dark current and low noise. Special device fabrication techniques and high quality wafer fusion reduce dark current to nano ampere level at unity gain, comparable to state-of-the-art commercial III/V APDs. The small excess noise is attributed to the large difference in ionization coefficients between electrons and holes in silicon. Detailed layer structure designs are developed specifically for fused InGaAs/Si APDs based on principles similar to those used in traditional InGaAs/InP APDs. An accurate yet straightforward technique for device structural parameters extraction is also proposed. The extracted results from the fabricated APDs agree with device design parameters. This agreement also confirms that the fusion interface has negligible effect on electric field distributions for devices fabricated from high quality fusion materials. The feasibility of fused InGaAs/Si APD for analog systems is also explored. Preliminary two-tone measurement shows that a moderately high dynamic range of 70 dBc/Hz1/2 for broadband Spur Free Dynamic Range (SFDR) or 82 dBc/Hz2/3 suboctave SFDR, up to 50 muA of optical current, can be achieved. The theoretical analyses of SNR show that fused InGaAs/Si APD receivers can provide larger Signal-to-Noise Ratio (SNR) than their III/V counterparts.
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AlInAsSb/GaSb staircase avalanche photodiode
NASA Astrophysics Data System (ADS)
Ren, Min; Maddox, Scott; Chen, Yaojia; Woodson, Madison; Campbell, Joe C.; Bank, Seth
2016-02-01
Over 30 years ago, Capasso and co-workers [IEEE Trans. Electron Devices 30, 381 (1982)] proposed the staircase avalanche photodetector (APD) as a solid-state analog of the photomultiplier tube. In this structure, electron multiplication occurs deterministically at steps in the conduction band profile, which function as the dynodes of a photomultiplier tube, leading to low excess multiplication noise. Unlike traditional APDs, the origin of staircase gain is band engineering rather than large applied electric fields. Unfortunately, the materials available at the time, principally AlxGa1-xAs/GaAs, did not offer sufficiently large conduction band offsets and energy separations between the direct and indirect valleys to realize the full potential of the staircase gain mechanism. Here, we report a true staircase APD operation using alloys of a rather underexplored material, AlxIn1-xAsySb1-y, lattice-matched to GaSb. Single step "staircase" devices exhibited a constant gain of ˜2×, over a broad range of applied bias, operating temperature, and excitation wavelengths/intensities, consistent with Monte Carlo calculations.
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NASA Technical Reports Server (NTRS)
Vasile, Stefan; Shera, Suzanne; Shamo, Denis
1998-01-01
New gamma ray and charged particle telescope designs based on scintillating fiber arrays could provide low cost, high resolution, lightweight, very large area and multi radiation length instrumentation for planned NASA space exploration. The scintillating fibers low visible light output requires readout sensors with single photon detection sensitivity and low noise. The sensitivity of silicon Avalanche Photodiodes (APDS) matches well the spectral output of the scintillating fibers. Moreover, APDs have demonstrated single photon capability. The global aim of our work is to make available to NASA a novel optical detector concept to be used as scintillating fiber readouts and meeting the requirements of the new generations of space-borne gamma ray telescopes. We proposed to evaluate the feasibility of using RMD's small area APDs ((mu)APD) as scintillating fiber readouts and to study possible alternative (mu)APD array configurations for space borne readout scintillating fiber systems, requiring several hundred thousand to one million channels. The evaluation has been conducted in accordance with the task description and technical specifications detailed in the NASA solicitation "Studies of Avalanche Photodiodes (APD as readout devices for scintillating fibers for High Energy Gamma-Ray Astronomy Telescopes" (#8-W-7-ES-13672NAIS) posted on October 23, 1997. The feasibility study we propose builds on recent developments of silicon APD arrays and light concentrators advances at RMD, Inc. and on more than 5 years of expertise in scintillating fiber detectors. In a previous program we carried out the initial research to develop a high resolution, small pixel, solid-state, silicon APD array which exhibited very high sensitivity in the UV-VIS spectrum. This (mu)APD array is operated in Geiger mode and results in high gain (greater than 10(exp 8)), extremely low noise, single photon detection capability, low quiescent power (less than 10 (mu)W/pixel for 30 micrometers sensitive area diameter) and output in the 1-5 volt range. If successful, this feasibility study will make possible the development of a scintillating fiber detector with unsurpassed sensitivity, extremely low power usage, a crucial factor of merit for space based sensors and telescopes.
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The Diagnosis and Management of Auditory Processing Disorder
ERIC Educational Resources Information Center
Moore, David R.
2011-01-01
Purpose: To provide a personal perspective on auditory processing disorder (APD), with reference to the recent clinical forum on APD and the needs of clinical speech-language pathologists and audiologists. Method: The Medical Research Council-Institute of Hearing Research (MRC-IHR) has been engaged in research into APD and auditory learning for 8…
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45 CFR 307.5 - Mandatory computerized support enforcement systems.
Code of Federal Regulations, 2010 CFR
2010-10-01
.... Waiver requests must be submitted and approved as part of the State's APD or APD update. (c) Conditions... chapter; and either: (2) The waiver request meets the criteria set forth in section 1115(c) (1), (2) and... system configuration. APDs submitted by States which include requests for waiver for an alternative...
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45 CFR 307.5 - Mandatory computerized support enforcement systems.
Code of Federal Regulations, 2011 CFR
2011-10-01
.... Waiver requests must be submitted and approved as part of the State's APD or APD update. (c) Conditions... chapter; and either: (2) The waiver request meets the criteria set forth in section 1115(c) (1), (2) and... system configuration. APDs submitted by States which include requests for waiver for an alternative...
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NASA Astrophysics Data System (ADS)
Wang, Shuai; Sun, Huayan; Guo, Huichao
2018-01-01
Aiming at the problem of beam scanning in low-resolution APD array in three-dimensional imaging, a method of beam scanning with liquid crystal phase-space optical modulator is proposed to realize high-resolution imaging by low-resolution APD array. First, a liquid crystal phase spatial light modulator is used to generate a beam array and then a beam array is scanned. Since the sub-beam divergence angle in the beam array is smaller than the field angle of a single pixel in the APD array, the APD's pixels respond only to the three-dimensional information of the beam illumination position. Through the scanning of the beam array, a single pixel is used to collect the target three-dimensional information multiple times, thereby improving the resolution of the APD detector. Finally, MATLAB is used to simulate the algorithm in this paper by using two-dimensional scalar diffraction theory, which realizes the splitting and scanning with a resolution of 5 x 5. The feasibility is verified theoretically.
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Theoretical Studies on InGaAs/InAlAs SAGCM Avalanche Photodiodes
NASA Astrophysics Data System (ADS)
Cao, Siyu; Zhao, Yue; ur Rehman, Sajid; Feng, Shuai; Zuo, Yuhua; Li, Chuanbo; Zhang, Lichun; Cheng, Buwen; Wang, Qiming
2018-05-01
In this paper, we provide a detailed insight on InGaAs/InAlAs separate absorption, grading, charge, and multiplication avalanche photodiodes (SAGCM APDs) and a theoretical model of APDs is built. Through theoretical analysis and two-dimensional (2D) simulation, the influence of charge layer and tunneling effect on the APDs is fully understood. The design of charge layer (including doping level and thickness) can be calculated by our predictive model for different multiplication thickness. We find that as the thickness of charge layer increases, the suitable doping level range in charge layer decreases. Compared to thinner charge layer, performance of APD varies significantly via several percent deviations of doping concentrations in thicker charge layer. Moreover, the generation rate ( G btt ) of band-to-band tunnel is calculated, and the influence of tunneling effect on avalanche field was analyzed. We confirm that avalanche field and multiplication factor ( M n ) in multiplication will decrease by the tunneling effect. The theoretical model and analysis are based on InGaAs/InAlAs APD; however, they are applicable to other APD material systems as well.
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Gastrin producing G-cells after chronic ethanol and low protein nutrition.
Koko, V; Todorović, V; Varagić, J; Micev, M; Korać, A; Bajcetić, M; Cakić-Milosević, M; Nedeljković, M; Drndarević, N
1998-11-01
Male Wistar rats, (2 months old), randomly divided according to the diet offered to four groups (C-control; A- alcoholized, PD-protein-deprived, A-PD- alcoholized protein-deprived). In group A and A-PD rats, the number of gastrin producing G-cells was significantly lower. The volume density of G-cells was significantly decreased in alcoholic rats. Fasting serum gastrin level (FSGL) significantly raised due to combined effect of alcohol consumption and protein malnutrition. In group A rats, the profile area of G-cells and their nuclei increased. In PD rats, the profile area of G cells also increased. There were no differences in nucleus/cell ratio due to alcohol ingestion alone, but it decreased significantly in PD and A-PD rats. Pale and lucent types of granules were predominantly seen in G-cells of animals of group A and A-PD. Mean diameter of granules increased in A, PD and A-PD rats. Other endocrine cells (ECL, D, EC) also decreased in number in A rats. Somatostatin producing D-cells decreased significantly in A-PD rats, both in fundic and pyloric mucosa.
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NASA Astrophysics Data System (ADS)
Deng, Dongdong; Murphy, Michael J.; Hakim, Joe B.; Franceschi, William H.; Zahid, Sohail; Pashakhanloo, Farhad; Trayanova, Natalia A.; Boyle, Patrick M.
2017-09-01
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, causing morbidity and mortality in millions worldwide. The atria of patients with persistent AF (PsAF) are characterized by the presence of extensive and distributed atrial fibrosis, which facilitates the formation of persistent reentrant drivers (RDs, i.e., spiral waves), which promote fibrillatory activity. Targeted catheter ablation of RD-harboring tissues has shown promise as a clinical treatment for PsAF, but the outcomes remain sub-par. Personalized computational modeling has been proposed as a means of non-invasively predicting optimal ablation targets in individual PsAF patients, but it remains unclear how RD localization dynamics are influenced by inter-patient variability in the spatial distribution of atrial fibrosis, action potential duration (APD), and conduction velocity (CV). Here, we conduct simulations in computational models of fibrotic atria derived from the clinical imaging of PsAF patients to characterize the sensitivity of RD locations to these three factors. We show that RDs consistently anchor to boundaries between fibrotic and non-fibrotic tissues, as delineated by late gadolinium-enhanced magnetic resonance imaging, but those changes in APD/CV can enhance or attenuate the likelihood that an RD will anchor to a specific site. These findings show that the level of uncertainty present in patient-specific atrial models reconstructed without any invasive measurements (i.e., incorporating each individual's unique distribution of fibrotic tissue from medical imaging alongside an average representation of AF-remodeled electrophysiology) is sufficiently high that a personalized ablation strategy based on targeting simulation-predicted RD trajectories alone may not produce the desired result.
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Yin, Chunxia; Chen, Yaoxu; Wu, Huanlin; Xu, Danping; Tan, Wen
2017-12-01
Isosteviol has been demonstrated to play a protective role during ischemia reperfusion (I/R) myocardial infarction. However, the underlying electrophysiological mechanisms of isosteviol are still unknown. Our previous study showed that the rapid component of the delayed rectifier potassium channel (I Kr ) plays an important role in the prolongation of I/R-induced QT interval-related arrhythmia. This study aimed to investigate whether isosteviol could attenuate I/R-induced prolongation of the action potential duration (APD) along with inhibition of I Kr , and we aimed to clarify the electrophysiological mechanism of isosteviol to determine its cardioprotective effects in guinea pigs. We observed that the APD 90 were 298.5±41.6ms in control, 528.6±56.7ms during I/R, and reduced to 327.8±40.5ms after 10μmol/L of isosteviol treatment. The I Kr currents were 1.44±0.06 pA·pF -1 in the control group, 0.50±0.07pA·pF -1 during I/R, and recovered to 1.20±0.12pA·pF -1 after 10μmol/L of isoteviol treatment. Moreover, isosteviol reduced the over-production of reactive oxygen species (ROS) during I/R. Importantly, isosteviol does not affect the I Kr and human ether-a-go-go-related gene currents of normal cardiomyocytes. It attenuated the I/R-induced inhibition of I Kr due to reduced over-production of ROS. Furthermore, isosteviol is safe and has no cardiotoxicity, and it might be beneficial for coronary reperfusion therapy. Copyright © 2017. Published by Elsevier B.V.
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Serrano, Ana; Rangel, Nairy; Carrizo, Edgardo; Uzcátegui, Euderruh; Sandia, Ignacio; Zabala, Angélica; Fernández, Erika; Tálamo, Eduardo; Servigna, Mercedes; Prieto, Dexi; Connell, Lisette; Baptista, Trino
2014-02-01
The antipsychotic drug (APD) clozapine (CLZ) is under-prescribed because of concerns about its safety. We evaluated in separate protocols the frequency of cardiomyopathy and hyponatraemia, which are adverse drug effects, where few comparative studies are available. Cross-sectional studies in subjects treated for at least 3 consecutive months with the same drug were conducted. Cardiomyopathy: Patients undergoing treatment either with CLZ (n = 125) or with other typical or atypical APDs (n = 59) were examined by a cardiologist who also recorded echocardiograms and electrocardiograms in order to diagnose cardiomyopathy. Hyponatraemia: Fasting sodium levels were assessed in patients receiving any of the following treatments: CLZ (n = 88), other atypical APDs (n = 61), typical APDs (n = 23), typical + atypical APDs (n = 11), and other drugs/drug-free (n = 36). Cardiomyopathy: No case of cardiomyopathy was detected. The frequency of abnormal ventricular ejection fraction (< 55%) was similar in both treatment groups (p = 1). Hyponatraemia: The frequency of hyponatraemia (percentage; 95% CI) was: CLZ (3.4%; -0.7, 7.1); other atypical APDs (4.9%; -0.5, 10.3); typical APDs (26.1%; 8.2, 44.0); typical + atypical APDs (9.1%; -7.8, 26.0); other drugs/drug-free (0%). None of the CLZ hyponatraemia subjects were on monotherapy. Our results are at odds with previous studies of CLZ-associated cardiomyopathy. However, they must be compared to further cross-sectional or prospective studies because most published data come from either case reports or pharmacovigilance systems. The frequency of hyponatraemia during CLZ administration was similar to that observed with other atypical APDs, and it was significantly lower than that recorded with typical agents. These results, along with numerous case reports on the effects of CLZ in patients with polydipsia and water intoxication, point to a safe or even positive profile of CLZ on electrolytic regulation.
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FDG PET/CT findings in acquired perforating dermatosis.
Shinmura, Akiko; Abe, Koichiro; Baba, Shingo; Isoda, Takuro; Maruoka, Yasuhiro; Yasukawa, Fumiko; Kiryu, Hiromaro; Sasaki, Masayuki; Furue, Masutaka; Honda, Hiroshi
2012-10-01
Acquired perforating dermatosis (APD) is an uncommon cutaneous perforating disorder. We report a patient on hemodialysis who developed skin eruption and jaundice. He underwent FDG PET/CT under suspicion of biliary malignancies. PET/CT showed no significant abnormal uptake except of multiple FDG-avid nodules in the skin. The eruption he had was histopathologically diagnosed as APD by skin biopsy. His case suggests that APD should be considered as a differential diagnosis when multiple cutaneous FDG accumulations are found in a patient on hemodialysis. To the best of our knowledge, this is the first report showing the FDG PET/CT findings of APD.
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The technology on noise reduction of the APD detection circuit
NASA Astrophysics Data System (ADS)
Wu, Xue-ying; Zheng, Yong-chao; Cui, Jian-yong
2013-09-01
The laser pulse detection is widely used in the field of laser range finders, laser communications, laser radar, laser Identification Friend or Foe, et al, for the laser pulse detection has the advantage of high accuracy, high sensitivity and strong anti-interference. The avalanche photodiodes (APD) has the advantage of high quantum efficiency, high response speed and huge gain. The APD is particularly suitable for weak signal detection. The technology that APD acts as the photodetector for weak signal reception and amplification is widely used in laser pulse detection. The APD will convert the laser signal to weak electrical signal. The weak signal is amplified, processed and exported by the circuit. In the circuit design, the optimal signal detection is one key point in photoelectric detection system. The issue discusses how to reduce the noise of the photoelectric signal detection circuit and how to improve the signal-to-noise ratio, related analysis and practice included. The essay analyzes the mathematical model of the signal-to-noise ratio for photoelectric conversion and the noise of the APD photoelectric detection system. By analysis the bandwidth of the detection system is determined, and the circuit devices are selected that match the APD. In the circuit design separated devices with low noise are combined with integrated operational amplifier for the purpose of noise reduction. The methods can effectively suppress the noise, and improve the detection sensitivity.
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Yin, Dechun; Hsieh, Yu-Cheng; Tsai, Wei-Chung; Wu, Adonis Zhi-Yang; Jiang, Zhaolei; Chan, Yi-Hsin; Xu, Dongzhu; Yang, Na; Shen, Changyu; Chen, Zhenhui; Lin, Shien-Fong; Chen, Peng-Sheng; Everett, Thomas H.
2017-01-01
Background Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small conductance calcium activated potassium currents (IKAS) are heterogeneously up-regulated in failing hearts. We hypothesized that IKAS influences the location and stability of rotors during VF. Methods and Results Optical mapping was performed on 9 rabbit hearts with pacing induced heart failure. The epicardial RV and LV were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the APD80 was determined and VF was induced. Areas with a greater than 50% increase in the maximum APD (ΔAPD) after apamin were considered to have a high IKAS distribution. At baseline, the distribution density of phase singularities (PS) during VF in high IKAS distribution areas was higher than in other areas (0.0035±.0011 vs 0.0014±0.0010 PS/pixel, P=0.004). In addition, high dominant frequencies (DF) also co-localized to high IKAS distribution areas (26.0 vs 17.9 Hz, P=0.003). These correlations were eliminated during VF after apamin infusion, as the number of PS (17.2 versus 11.0, P=0.009), and DFs (22.1 vs 16.2 Hz, P=0.022), were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion and the duration of VF decreased. Conclusions The IKAS current influences the mechanism of VF in failing hearts as PS, high DFs, and reentrant spiral waves all correlated to areas of high IKAS. Apamin eliminated this relationship and reduced VF vulnerability. PMID:28213506
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BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes.
Feldman, Arthur M; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Myers, Valerie D; Tilley, Douglas G; Gao, Erhe; Hoffman, Nicholas E; Tomar, Dhanendra; Madesh, Muniswamy; Rabinowitz, Joseph; Koch, Walter J; Su, Feifei; Khalili, Kamel; Cheung, Joseph Y
2016-03-01
Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 levels have been found to be reduced in end-stage non-familial failing myocardium. In contrast to neonatal myocytes in which BAG3 is found in the cytoplasm and involved in protein quality control and apoptosis, in adult mouse left ventricular (LV) myocytes BAG3 co-localized with Na(+)-K(+)-ATPase and L-type Ca(2+) channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitated with β1-adrenergic receptor, L-type Ca(2+) channels and phospholemman. To simulate decreased BAG3 protein levels observed in human heart failure, we targeted BAG3 by shRNA (shBAG3) in adult LV myocytes. Reducing BAG3 by 55% resulted in reduced contraction and [Ca(2+)]i transient amplitudes in LV myocytes stimulated with isoproterenol. L-type Ca(2+) current (ICa) and sarcoplasmic reticulum (SR) Ca(2+) content but not Na(+)/Ca(2+) exchange current (INaCa) or SR Ca(2+) uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyryl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes, consistent with BAG3 having effects upstream and at the level of the receptor. Resting membrane potential and action potential amplitude were unaffected but APD50 and APD90 were prolonged in shBAG3 myocytes. Protein levels of Ca(2+) entry molecules and other important excitation-contraction proteins were unchanged in myocytes with lower BAG3. Our findings that BAG3 is localized at the sarcolemma and t-tubules while modulating myocyte contraction and action potential duration through specific interaction with the β1-adrenergic receptor and L-type Ca(2+) channel provide novel insight into the role of BAG3 in cardiomyopathies and increased arrhythmia risks in heart failure. Copyright © 2016 Elsevier Ltd. All rights reserved.
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BAG3 regulates contractility and Ca2+ homeostasis in adult mouse ventricular myocytes
Feldman, Arthur M.; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Myers, Valerie D.; Tilley, Douglas G.; Gao, Erhe; Hoffman, Nicholas E.; Tomar, Dhanendra; Madesh, Muniswamy; Rabinowitz, Joseph; Koch, Walter J.; Su, Feifei; Khalili, Kamel; Cheung, Joseph Y.
2016-01-01
Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 levels have been found to be reduced in end-stage non-familial failing myocardium. In contrast to neonatal myocytes in which BAG3 is found in the cytoplasm and involved in protein quality control and apoptosis, in adult mouse left ventricular (LV) myocytes BAG3 co-localized with Na+-K+-ATPase and L-type Ca2+ channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitated with β1-adrenergic receptor, L-type Ca2+ channels and phospholemman. To simulate decreased BAG3 protein levels observed in human heart failure, we targeted BAG3 by shRNA (shBAG3) in adult LV myocytes. Reducing BAG3 by 55% resulted in reduced contraction and [Ca2+]i transient amplitudes in LV myocytes stimulated with isoproterenol. L-type Ca2+ current (ICa) and sarcoplasmic reticulum (SR) Ca2+ content but not Na+/Ca2+ exchange current (INaCa) or SR Ca2+ uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyrl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes, consistent with BAG3 having effects upstream and at the level of the receptor. Resting membrane potential and action potential amplitude were unaffected but APD50 and APD90 were prolonged in shBAG3 myocytes. Protein levels of Ca2+ entry molecules and other important excitation-contraction proteins were unchanged in myocytes with lower BAG3. Our findings that BAG3 is localized at the sarcolemma and t-tubules while modulating myocyte contraction and action potential duration through specific interaction with the β1-adrenergic receptor and L-type Ca2+ channel provide novel insight into the role of BAG3 in cardiomyopathies and increased arrhythmia risks in heart failure. PMID:26796036
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30 CFR 250.418 - What additional information must I submit with my APD?
Code of Federal Regulations, 2012 CFR
2012-07-01
..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Applying for A Permit to Drill § 250.418 What additional information must I submit with my APD? You must include the following with the APD: (a) Rated capacities of the drilling rig...
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30 CFR 250.418 - What additional information must I submit with my APD?
Code of Federal Regulations, 2014 CFR
2014-07-01
..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Applying for A Permit to Drill § 250.418 What additional information must I submit with my APD? You must include the following with the APD: (a) Rated capacities of the drilling rig...
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30 CFR 250.418 - What additional information must I submit with my APD?
Code of Federal Regulations, 2013 CFR
2013-07-01
..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Applying for A Permit to Drill § 250.418 What additional information must I submit with my APD? You must include the following with the APD: (a) Rated capacities of the drilling rig...
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30 CFR 250.418 - What additional information must I submit with my APD?
Code of Federal Regulations, 2010 CFR
2010-07-01
... INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Oil and Gas Drilling Operations Applying for A Permit to Drill § 250.418 What additional information must I submit with my APD? You must include the following with the APD: (a) Rated capacities of the drilling rig and major...
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Liu, H; Ji, M; Jiang, H; Liu, L; Hua, W; Chen, K; Ji, R
2000-10-02
Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Based on our previous studies, a set of 17 methylsulfonamido phenylethylamine analogues were investigated by 3D-QSAR techniques of CoMFA and CoMSIA. The 3D-QSAR models proved a good predictive ability, and could describe the steric, electrostatic and hydrophobic requirements for recognition forces of the receptor site. According to the clues provided by this 3D-QSAR analysis, we designed and synthesized a series of new analogues of methanesulfonamido phenylethylamine (VIa-i). Pharmacological assay indicated that the effective concentrations of delaying the functional refractory period (FRP) 10ms of these new compounds have a good correlation with the 3D-QSAR predicted values. It is remarkable that the maximal percent change of delaying FRP in microM of compound VIc is much higher than that of dofetilide. The results showed that the 3D-QSAR models are reliable.
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Carro, Jesús; Rodríguez-Matas, José F; Monasterio, Violeta; Pueyo, Esther
2017-10-01
Models of ion channel dynamics are usually built by fitting isolated cell experimental values of individual parameters while neglecting the interaction between them. Another shortcoming regards the estimation of ionic current conductances, which is often based on quantification of Action Potential (AP)-derived markers. Although this procedure reduces the uncertainty in the calculation of conductances, many studies evaluate electrophysiological AP-derived markers from single cell simulations, whereas experimental measurements are obtained from tissue preparations. In this work, we explore the limitations of these approaches to estimate ion channel dynamics and maximum current conductances and how they could be overcome by using multiscale simulations of experimental protocols. Four human ventricular cell models, namely ten Tusscher and Panfilov (2006), Grandi et al. (2010), O'Hara et al. (2011), and Carro et al. (2011), were used. Two problems involving scales from ion channels to tissue were investigated: 1) characterization of L-type calcium voltage-dependent inactivation I Ca,L ; 2) identification of major ionic conductance contributors to steady-state AP markers, including APD 90 , APD 75 , APD 50 , APD 25 , Triangulation and maximal and minimal values of V and dV/dt during the AP (V max , V min , dV/dt max , dV/dt min ). Our results show that: 1) I Ca,L inactivation characteristics differed significantly when calculated from model equations and from simulations reproducing the experimental protocols. 2) Large differences were found in the ionic currents contributors to APD 25 , Triangulation, V max , dV/dt max and dV/dt min between single cells and 1D-tissue. When proposing any new model formulation, or evaluating an existing model, consistency between simulated and experimental data should be verified considering all involved effects and scales. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Melo, Ândrea de; Mezzomo, Carolina Lisbôa; Garcia, Michele Vargas; Biaggio, Eliara Pinto Vieira
2018-01-01
Introduction Computerized auditory training (CAT) has been building a good reputation in the stimulation of auditory abilities in cases of auditory processing disorder (APD). Objective To measure the effects of CAT in students with APD, with typical or atypical phonological acquisition, through electrophysiological and subjective measures, correlating them pre- and post-therapy. Methods The sample for this study includes14 children with APD, subdivided into children with APD and typical phonological acquisition (G1), and children with APD and atypical phonological acquisition (G2). Phonological evaluation of children (PEC), long latency auditory evoked potential (LLAEP) and scale of auditory behaviors (SAB) were conducted to help with the composition of the groups and with the therapeutic intervention. The therapeutic intervention was performed using the software Escuta Ativa (CTS Informática, Pato Branco, Brazil) in 12 sessions of 30 minutes, twice a week. For data analysis, the appropriate statistical tests were used. Results A decrease in the latency of negative wave N2 and the positive wave P3 in the left ear in G1, and a decrease of P2 in the right ear in G2 were observed. In the analysis comparing the pre- and post-CAT groups, there was a significant difference in P1 latency in the left ear and P2 latency in the right ear, pre-intervention. Furthermore, eight children had an absence of the P3 wave, pre-CAT, but after the intervention, all of them presented the P3 wave. There were changes in the SAB score pre- and post-CAT in both groups. The presence of correlation between the scale and some LLAEP components was observed. Conclusion The CAT produced an electrophysiological modification, which became evident in the effects of the effects of neural plasticity after CAT. The SAB proved to be useful in measuring the therapeutic effects of the intervention. Moreover, there were behavioral changes in the SAB (higher scores) and correlation with LLAEP.
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A Highly Sensitive Multi-Element HgCdTe E-APD Detector for IPDA Lidar Applications
NASA Technical Reports Server (NTRS)
Beck, Jeff; Welch, Terry; Mitra, Pradip; Reiff, Kirk; Sun, Xiaoli; Abshire, James
2014-01-01
An HgCdTe electron avalanche photodiode (e-APD) detector has been developed for lidar receivers, one application of which is integrated path differential absorption lidar measurements of such atmospheric trace gases as CO2 and CH4. The HgCdTe APD has a wide, visible to mid-wave-infrared, spectral response, high dynamic range, substantially improved sensitivity, and an expected improvement in operational lifetime. A demonstration sensor-chip assembly consisting of a 4.3 lm cutoff HgCdTe 4 9 4 APD detector array with 80 micrometer pitch pixels and a custom complementary metal-oxide-semiconductor readout integrated circuit was developed. For one typical array the APD gain was 654 at 12 V with corresponding gain normalized dark currents ranging from 1.2 fA to 3.2 fA. The 4 9 4 detector system was characterized at 77 K with a 1.55 micrometer wavelength, 1 microsecond wide, laser pulse. The measured unit gain detector photon conversion efficiency was 91.1%. At 11 V bias the mean measured APD gain at 77 K was 307.8 with sigma/mean uniformity of 1.23%. The average, noise-bandwidth normalized, system noise-equivalent power (NEP) was 1.04 fW/Hz(exp 1/2) with a sigma/mean of 3.8%. The measured, electronics-limited, bandwidth of 6.8 MHz was more than adequate for 1 microsecond pulse detection. The system had an NEP (3 MHz) of 0.4 fW/Hz(exp 1/2) at 12 V APD bias and a linear dynamic range close to 1000. A gain-independent quantum-limited SNR of 80% of full theoretical was indicative of a gain-independent excess noise factor very close to 1.0 and the expected APD mode quantum efficiency.
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[Short-term sentence memory in children with auditory processing disorders].
Kiese-Himmel, C
2010-05-01
To compare sentence repetition performance of different groups of children with Auditory Processing Disorders (APD) and to examine the relationship between age or respectively nonverbal intelligence and sentence recall. Nonverbal intelligence was measured with the COLOURED MATRICES, in addition the children completed a standardized test of SENTENCE REPETITION (SR) which requires to repeat spoken sentences (subtest of the HEIDELBERGER SPRACHENTWICKLUNGSTEST). Three clinical groups (n=49 with monosymptomatic APD; n=29 with APD+developmental language impairment; n=14 with APD+developmental dyslexia); two control groups (n=13 typically developing peers without any clinical developmental disorder; n=10 children with slight reduced nonverbal intelligence). The analysis showed a significant group effect (p=0.0007). The best performance was achieved by the normal controls (T-score 52.9; SD 6.4; Min 42; Max 59) followed by children with monosymptomatic APD (43.2; SD 9.2), children with the co-morbid-conditions APD+developmental dyslexia (43.1; SD 10.3), and APD+developmental language impairment (39.4; SD 9.4). The clinical control group presented the lowest performance, on average (38.6; SD 9.6). Accordingly, language-impaired children and children with slight reductions in intelligence could poorly use their grammatical knowledge for SR. A statistically significant improvement in SR was verified with the increase of age with the exception of children belonging to the small group with lowered intelligence. This group comprised the oldest children. Nonverbal intelligence correlated positively with SR only in children with below average-range intelligence (0.62; p=0.054). The absence of APD, SLI as well as the presence of normal intelligence facilitated the use of phonological information for SR.
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Pihlaja, Rea; Takkinen, Jatta; Eskola, Olli; Vasara, Jenni; López-Picón, Francisco R; Haaparanta-Solin, Merja; Rinne, Juha O
2015-04-28
Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice. Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment. JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.
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Microstructural observations in rapidly-solidified and heat-treated Ni3Al-Cr alloys
DOE Office of Scientific and Technical Information (OSTI.GOV)
Carro, G.; Flanagan, W.F.
1992-08-01
The microstructural development following heat treatments of several rapidly-solidified Ni3Al-Cr and Ni3Al-Cr-B alloys is presented. Depending on composition, the as-solidified samples were either 100 percent gamma-prime phase - in the form of fine antiphase domains (APD) - or a mixture of gamma-prime (APDs) and beta phases. Upon annealing, the as-solidified microstructures transform to either APD-free gamma-prime or mixtures of gamma and gamma-prime phases. For those compositions where the quenched microstructures were 100 percent gamma-prime it was observed that APD coarsening followed conventional grain-growth kinetics, but when gamma phase precipitated on the APD boundaries the rate constant changed abruptly while themore » time exponent remained unaffected. It was also found that alloys containing critical amounts of chromium and boron are susceptible to precipitation of the boride Cr5B3. 14 refs.« less
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Microstructural observations in rapidly-solidified and heat-treated Ni sub 3 Al-Cr alloys
DOE Office of Scientific and Technical Information (OSTI.GOV)
Carro, G.; Flanagan, W.F.
1992-01-01
In this paper , the microstructural development following heat treatments of several rapidly-solidified Ni{sub 3}Al-Cr and Ni{sub 3}Al-Cr-B alloys is presented. Depending on composition, the as-solidified samples were either 100% {gamma} phase-in the form of fine anti-phase domains (APD)-or a mixture of {gamma} (APDs) and {beta} phases. Upon annealing, the as-solidified microstructures transform to either APD-free {gamma}or mixtures of {gamma}and {gamma}{prime} phases. For those compositions where the quenched microstructures were 100{gamma}{prime} it was observed that APD coarsening followed conventional grain-growth kinetics, but when {gamma} phase precipitated on the APD boundaries the rate constant changed abruptly while the time exponent remainedmore » unaffected. It was also found that alloys containing critical amounts of chromium and boron are susceptible to precipitation of the boride Cr{sub 5}B{sub 3}.« less
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Microstructural observations in rapidly-solidified and heat-treated Ni3Al-Cr alloys
NASA Technical Reports Server (NTRS)
Carro, G.; Flanagan, W. F.
1992-01-01
The microstructural development following heat treatments of several rapidly-solidified Ni3Al-Cr and Ni3Al-Cr-B alloys is presented. Depending on composition, the as-solidified samples were either 100 percent gamma-prime phase - in the form of fine antiphase domains (APD) - or a mixture of gamma-prime (APDs) and beta phases. Upon annealing, the as-solidified microstructures transform to either APD-free gamma-prime or mixtures of gamma and gamma-prime phases. For those compositions where the quenched microstructures were 100 percent gamma-prime it was observed that APD coarsening followed conventional grain-growth kinetics, but when gamma phase precipitated on the APD boundaries the rate constant changed abruptly while the time exponent remained unaffected. It was also found that alloys containing critical amounts of chromium and boron are susceptible to precipitation of the boride Cr5B3.
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Effect of electron irradiation dose on the performance of avalanche photodiode electron detectors
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kawauchi, Taizo; Wilde, Markus; Fukutani, Katsuyuki
2009-01-01
Avalanche photodiodes (APDs) are efficient detectors for electrons with energies below 100 keV. The damaging effects of 8 keV electron beam irradiation on the dark current and the output signal of the APD detector were investigated in this study. The APD dark current increases after electron doses exceeding 1.4x10{sup 13} cm{sup -2}. Preirradiation by high doses of 8 keV electrons further causes a deformation of the pulse height distribution of the APD output in the subsequent detection of low-flux electrons. This effect is particularly prominent when the energy of the detected electrons is lower than that of the damaging electrons.more » By comparing the experimental data with results of a simulation based on an electron trapping model, we conclude that the degradation of the APD performance is attributable to an enhancement of secondary-electron trapping at irradiation induced defects.« less
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Alpay Ates, M; Algul, Ayhan; Semiz, Umit B; Gecici, Omer; Basoglu, Cengiz; Ebrinc, Servet; Cetin, Mesut
2011-05-01
The aims of this study were to determine the characteristics of self-mutilation (SM) and examine the relationship between SM and psychopathy in male subjects with antisocial personality disorder (APD). APD diagnosis was established by the Structured Clinical Interview for DSM-III-R Axis II Disorders. Subjects (N = 116) were assessed using the Psychopathy Checklist-Revised and a semi-structured self-mutilation questionnaire form. In males with APD, the percentages of psychopathy and SM were 48.3% (N =56) and 96.6% (N = 112), respectively. There were positive correlations between severity of psychopathy and severity, number, and frequency of SM. Considerably high rates of SM and psychopathy were found in Turkish males with APD. The features of SM were associated with comorbidity of psychopathy. These results showed the importance of exploring the self-injurious behavior and psychopathy when diagnosed with APD.
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Auditory processing disorders: an update for speech-language pathologists.
DeBonis, David A; Moncrieff, Deborah
2008-02-01
Unanswered questions regarding the nature of auditory processing disorders (APDs), how best to identify at-risk students, how best to diagnose and differentiate APDs from other disorders, and concerns about the lack of valid treatments have resulted in ongoing confusion and skepticism about the diagnostic validity of this label. This poses challenges for speech-language pathologists (SLPs) who are working with school-age children and whose scope of practice includes APD screening and intervention. The purpose of this article is to address some of the questions commonly asked by SLPs regarding APDs in school-age children. This article is also intended to serve as a resource for SLPs to be used in deciding what role they will or will not play with respect to APDs in school-age children. The methodology used in this article included a computerized database review of the latest published information on APD, with an emphasis on the work of established researchers and expert panels, including articles from the American Speech-Language-Hearing Association and the American Academy of Audiology. The article concludes with the authors' recommendations for continued research and their views on the appropriate role of the SLP in performing careful screening, making referrals, and supporting intervention.
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NASA Astrophysics Data System (ADS)
Suvarna, Puneet Harischandra
Solar-blind ultraviolet avalanche photodiodes are an enabling technology for applications in the fields of astronomy, communication, missile warning systems, biological agent detection and particle physics research. Avalanche photodiodes (APDs) are capable of detecting low-intensity light with high quantum efficiency and signal-to-noise ratio without the need for external amplification. The properties of III-N materials (GaN and AlGaN) are promising for UV photodetectors that are highly efficient, radiation-hard and capable of visible-blind or solar-blind operation without the need for external filters. However, the realization of reliable and high performance III-N APDs and imaging arrays has several technological challenges. The high price and lack of availability of bulk III-N substrates necessitates the growth of III-Ns on lattice mismatched substrates leading to a high density of dislocations in the material that can cause high leakage currents, noise and premature breakdown in APDs. The etched sidewalls of III-N APDs and high electric fields at contact edges are also detrimental to APD performance and reliability. In this work, novel technologies have been developed and implemented that address the issues of performance and reliability in III-Nitride based APDs. To address the issue of extended defects in the bulk of the material, a novel pulsed MOCVD process was developed for the growth of AlGaN. This process enables growth of high crystal quality AlxGa1-xN with excellent control over composition, doping and thickness. The process has also been adapted for the growth of high quality III-N materials on silicon substrate for devices such as high electron mobility transistors (HEMTs). A novel post-growth defect isolation technique is also discussed that can isolate the impact of conductive defects from devices. A new sidewall passivation technique using atomic layer deposition (ALD) of dielectric materials was developed for III-N APDs that is effective in reducing the dark-current and trap states at sidewalls by close to an order of magnitude, leading to improved APD performance. Development and implementation of an ion implantation based contact edge termination technique for III-N APDs that helps prevent premature breakdown from the contact edge of the devices, has further lead to improved reliability. Finally novel improved III-N APD device designs are proposed using preliminary experiments and numerical simulations for future implementations.
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The Association between Peritoneal Dialysis Modality and Peritonitis
Johnson, David W.; McDonald, Stephen P.; Boudville, Neil; Borlace, Monique; Badve, Sunil V.; Sud, Kamal; Clayton, Philip A.
2014-01-01
Background and objectives There is conflicting evidence comparing peritonitis rates among patients treated with continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD). This study aims to clarify the relationship between peritoneal dialysis (PD) modality (APD versus CAPD) and the risk of developing PD-associated peritonitis. Design, setting, participants, & measurements This study examined the association between PD modality (APD versus CAPD) and the risks, microbiology, and clinical outcomes of PD-associated peritonitis in 6959 incident Australian PD patients between October 1, 2003, and December 31, 2011, using data from the Australia and New Zealand Dialysis and Transplant Registry. Median follow-up time was 1.9 years. Results Patients receiving APD were younger (60 versus 64 years) and had fewer comorbidities. There was no association between PD modality and time to first peritonitis episode (adjusted hazard ratio [HR] for APD versus CAPD, 0.98; 95% confidence interval [95% CI], 0.91 to 1.07; P=0.71). However, there was a lower hazard of developing Gram-positive peritonitis with APD than CAPD, which reached borderline significance (HR, 0.90; 95% CI, 0.80 to 1.00; P=0.05). No statistically significant difference was found in the risk of hospitalizations (odds ratio, 1.12; 95% CI, 0.93 to 1.35; P=0.22), but there was a nonsignificant higher likelihood of 30-day mortality (odds ratio, 1.33; 95% CI, 0.93 to 1.88; P=0.11) at the time of the first episode of peritonitis for patients receiving APD. For all peritonitis episodes (including subsequent episodes of peritonitis), APD was associated with lower rates of culture-negative peritonitis (incidence rate ratio [IRR], 0.81; 95% CI, 0.69 to 0.94; P=0.002) and higher rates of gram-negative peritonitis (IRR, 1.28; 95% CI, 1.13 to 1.46; P=0.01). Conclusions PD modality was not associated with a higher likelihood of developing peritonitis. However, APD was associated with a borderline reduction in the likelihood of a first episode of Gram-positive peritonitis compared with CAPD, and with lower rates of culture-negative peritonitis and higher rates of Gram-negative peritonitis. Peritonitis outcomes were comparable between both modalities. PMID:24626434
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Südmeyer, Martin; Antke, Christina; Zizek, Tanja; Beu, Markus; Nikolaus, Susanne; Wojtecki, Lars; Schnitzler, Alfons; Müller, Hans-Wilhelm
2011-05-01
In vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration and sympathetic cardiac innervation with SPECT is used to distinguish idiopathic Parkinson disease (PD) from atypical parkinsonian disorder (APD). However, the diagnostic accuracy of these imaging approaches as stand-alone procedures is often unsatisfying. The aim of this study was therefore to evaluate to which extent diagnostic accuracy can be increased by their combined use together with a multidimensional statistical algorithm. The SPECT radiotracers (123)I-(S)-2-hydroxy-3-iodo-6-methoxy-N-[1-ethyl-2-pyrrodinyl)-methyl]benzamide (IBZM), (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropan (FP-CIT), and meta-(123)I-iodobenzylguanidine (MIBG) were used to assess striatal postsynaptic D(2) receptor binding, striatal presynaptic dopamine transporter binding, and myocardial adrenergic innervation, respectively. Thirty-one PD and 17 APD patients were prospectively investigated. PD and APD diagnoses were established using consensus criteria and reevaluated after 37.4 ± 12.4 and 26 ± 11.6 mo in PD and APD, respectively. Test accuracy (TA) for PD-APD differentiation was computed for all logical (Boolean) combinations of imaging modalities by receiver-operating-characteristic analysis--that is, after multidimensional optimization of cutoff values. Analysis showed moderate TA for PD-APD differentiation using each molecular approach alone (IBZM, 79%; MIBG, 73%; and FP-CIT, 73%). For combined use, the highest TA resulted under the assumption that at least 2 of the 3 biologic markers had to be positive for APD using the following cutoff values: 1.46 or less for IBZM, less than 2.10 for FP-CIT, and greater than 1.43 for MIBG. This algorithm distinguished APD from PD with a sensitivity of 94%, specificity of 94% (TA, 94%), positive predictive value of 89%, and negative predictive value of 97%. Results suggest that the multidimensional combination of FP-CIT, IBZM, and MIBG scintigraphy is likely to significantly increase TA in differentiating PD from APD. The differential diagnosis of degenerative parkinsonism may thus be facilitated.
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Low-Noise Free-Running High-Rate Photon-Counting for Space Communication and Ranging
NASA Technical Reports Server (NTRS)
Lu, Wei; Krainak, Michael A.; Yang, Guangning; Sun, Xiaoli; Merritt, Scott
2016-01-01
We present performance data for low-noise free-running high-rate photon counting method for space optical communication and ranging. NASA GSFC is testing the performance of two types of novel photon-counting detectors 1) a 2x8 mercury cadmium telluride (HgCdTe) avalanche array made by DRS Inc., and a 2) a commercial 2880-element silicon avalanche photodiode (APD) array. We successfully measured real-time communication performance using both the 2 detected-photon threshold and logic AND-gate coincidence methods. Use of these methods allows mitigation of dark count, after-pulsing and background noise effects without using other method of Time Gating The HgCdTe APD array routinely demonstrated very high photon detection efficiencies ((is) greater than 50%) at near infrared wavelength. The commercial silicon APD array exhibited a fast output with rise times of 300 ps and pulse widths of 600 ps. On-chip individually filtered signals from the entire array were multiplexed onto a single fast output. NASA GSFC has tested both detectors for their potential application for space communications and ranging. We developed and compare their performances using both the 2 detected photon threshold and coincidence methods.
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Low-Noise Free-Running High-Rate Photon-Counting for Space Communication and Ranging
NASA Technical Reports Server (NTRS)
Lu, Wei; Krainak, Michael A.; Yang, Guan; Sun, Xiaoli; Merritt, Scott
2016-01-01
We present performance data for low-noise free-running high-rate photon counting method for space optical communication and ranging. NASA GSFC is testing the performance of two types of novel photon-counting detectors 1) a 2x8 mercury cadmium telluride (HgCdTe) avalanche array made by DRS Inc., and a 2) a commercial 2880-element silicon avalanche photodiode (APD) array. We successfully measured real-time communication performance using both the 2 detected-photon threshold and logic AND-gate coincidence methods. Use of these methods allows mitigation of dark count, after-pulsing and background noise effects without using other method of Time Gating The HgCdTe APD array routinely demonstrated very high photon detection efficiencies (50) at near infrared wavelength. The commercial silicon APD array exhibited a fast output with rise times of 300 ps and pulse widths of 600 ps. On-chip individually filtered signals from the entire array were multiplexed onto a single fast output. NASA GSFC has tested both detectors for their potential application for space communications and ranging. We developed and compare their performances using both the 2 detected photon threshold and coincidence methods.
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Self-triggering readout system for the neutron lifetime experiment PENeLOPE
NASA Astrophysics Data System (ADS)
Gaisbauer, D.; Bai, Y.; Konorov, I.; Paul, S.; Steffen, D.
2016-02-01
PENeLOPE is a neutron lifetime measurement developed at the Technische Universität München and located at the Forschungs-Neutronenquelle Heinz Maier-Leibnitz (FRM II) aiming to achieve a precision of 0.1 seconds. The detector for PENeLOPE consists of about 1250 Avalanche Photodiodes (APDs) with a total active area of 1225 cm2. The decay proton detector and electronics will be operated at a high electrostatic potential of -30 kV and a magnetic field of 0.6 T. This includes shaper, preamplifier, ADC and FPGA cards. In addition, the APDs will be cooled to 77 K. The 1250 APDs are divided into 14 groups of 96 channels, including spares. A 12-bit ADC digitizes the detector signals with 1 MSps. A firmware was developed for the detector including a self-triggering readout with continuous pedestal calculation and configurable signal detection. The data transmission and configuration is done via the Switched Enabling Protocol (SEP). It is a time-division multiplexing low layer protocol which provides determined latency for time critical messages, IPBus, and JTAG interfaces. The network has a n:1 topology, reducing the number of optical links.
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Artificial Pancreas Device Systems for the Closed-Loop Control of Type 1 Diabetes
Trevitt, Sara; Simpson, Sue; Wood, Annette
2015-01-01
Background: Closed-loop artificial pancreas device (APD) systems are externally worn medical devices that are being developed to enable people with type 1 diabetes to regulate their blood glucose levels in a more automated way. The innovative concept of this emerging technology is that hands-free, continuous, glycemic control can be achieved by using digital communication technology and advanced computer algorithms. Methods: A horizon scanning review of this field was conducted using online sources of intelligence to identify systems in development. The systems were classified into subtypes according to their level of automation, the hormonal and glycemic control approaches used, and their research setting. Results: Eighteen closed-loop APD systems were identified. All were being tested in clinical trials prior to potential commercialization. Six were being studied in the home setting, 5 in outpatient settings, and 7 in inpatient settings. It is estimated that 2 systems may become commercially available in the EU by the end of 2016, 1 during 2017, and 2 more in 2018. Conclusions: There are around 18 closed-loop APD systems progressing through early stages of clinical development. Only a few of these are currently in phase 3 trials and in settings that replicate real life. PMID:26589628
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Rosenberg, Russell; Seiden, David J.; Hull, Steven G.; Erman, Milton; Schwartz, Howard; Anderson, Christen; Prosser, Warren; Shanahan, William; Sanchez, Matilde; Chuang, Emil; Roth, Thomas
2008-01-01
Introduction: Insomnia is a condition affecting 10% to 15% of the adult population and is characterized by difficulty falling asleep, difficulty staying asleep, or nonrestorative sleep, accompanied by daytime impairment or distress. This study evaluates APD125, a selective inverse agonist of the 5-HT2A receptor, for treatment of chronic insomnia, with particular emphasis on sleep maintenance. In phase 1 studies, APD125 improved sleep maintenance and was well tolerated. Methodology: Adult subjects (n = 173) with DSM-IV defined primary insomnia were randomized into a multicenter, double-blind, placebo-controlled, 3-way crossover study to compare 2 doses of APD125 (10 mg and 40 mg) with placebo. Each treatment period was 7 days with a 7- to 9-day washout period between treatments. Polysomnographic recordings were performed at the initial 2 screening nights and at nights (N) 1/2 and N 6/7 of each treatment period. Results: APD125 was associated with significant improvements in key sleep maintenance parameters measured by PSG. Wake time after sleep onset decreased (SEM) by 52.5 (3.2) min (10 mg) and 53.5 (3.5) min (40 mg) from baseline to N 1/2 vs. 37.8 (3.4) min for placebo, (P < 0.0001 for both doses vs placebo), and by 51.7 (3.4) min (P = 0.01) and 48.0 (3.6) min (P = 0.2) at N 6/7 vs. 44.0 (3.8) min for placebo. Significant APD125 effects on wake time during sleep were also seen (P < 0.0001 N 1/2, P < 0.001 N 6/7). The number of arousals and number of awakenings decreased significantly with APD125 treatment compared to placebo. Slow wave sleep showed a statistically significant dose-dependent increase. There was no significant decrease in latency to persistent sleep. No serious adverse events were reported, and no meaningful differences in adverse event profiles were observed between either dose of APD125 and placebo. APD125 was not associated with next-day psychomotor impairment as measured by Digit Span, Digit Symbol Copy, and Digit Symbol Coding Tests. Conclusions: APD125 produced statistically significant improvements in objective parameters of sleep maintenance and sleep consolidation and was well tolerated in adults with primary chronic insomnia. Citation: Rosenberg R; Seiden DJ; Hull SG; Erman M; Schwartz H; Anderson C; Prosser W; Shanahan W; Sanchez M; Chuang E; Roth T. APD125, a selective serotonin 5-HT2A receptor inverse agonist, significantly improves sleep maintenance in primary insomnia. SLEEP 2008;31(12):1663–1671. PMID:19090322
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Response of CMS avalanche photo-diodes to low energy neutrons
NASA Astrophysics Data System (ADS)
Brown, R. M.; Deiters, K.; Ingram, Q.; Renker, D.
2012-12-01
The response of the Avalanche Photo-diodes (APDs) installed in the CMS detector at the LHC to neutrons from 241AmBe and 252Cf sources is reported. Signals in size equivalent to those of up to 106 photo-electrons with the nominal APD gain are observed. Measurements with an APD with the protective epoxy coating removed and with the source placed behind the APD show that there is an important response due to recoil protons from neutron interactions with the hydrogen in the epoxy, in addition to signals from neutron interactions with the silicon of the diode. The effective gain of these signals is much smaller than the diode's nominal gain.
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Matsa, Elena; Dixon, James E; Medway, Christopher; Georgiou, Orestis; Patel, Minal J; Morgan, Kevin; Kemp, Paul J; Staniforth, Andrew; Mellor, Ian; Denning, Chris
2014-04-01
Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K(+) currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart.
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Matsa, Elena; Dixon, James E.; Medway, Christopher; Georgiou, Orestis; Patel, Minal J.; Morgan, Kevin; Kemp, Paul J.; Staniforth, Andrew; Mellor, Ian; Denning, Chris
2014-01-01
Aims Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS. Methods and results We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K+ currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations). Conclusions These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart. PMID:23470493
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NASA Astrophysics Data System (ADS)
Vasquez, Jaime; Saavedra, Arthur; Ramos, Roxana; Tavares, Pablo; Wade, Marcus; Fan, Sewan; Haag, Brooke
2013-04-01
Through the Research Scholars Institute, students of Hartnell Community College experimented with the application of avalanche photodiodes (APDs) as cosmic ray detectors during the summer of 2012. An APD detector was coupled with a 10 meter long wavelength shifting fiber (WSF) wrapped around a cylindrical plastic scintillator to maximize signal detection. A photomultiplier tube (PMT) was used in conjunction to detect the same scintillation light caused by incoming cosmic rays. Two APD detectors were evaluated to confirm the viability of the setup. In addition, a similar setup was recently utilized to implement multi-pixel photon counters (MPPCs) as readout detectors. Under this configuration, a high gain preamplifier was used to amplify the signals for both the MPPC and APD detectors. We report on our results characterizing the MPPC and discuss its overall performance. Compared to the APD, our findings suggest that the MPPC detector has greater sensitivity in detecting weak light signals, and can be used in place of the PMT for certain counting applications.
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APDS: Autonomous Pathogen Detection System
DOE Office of Scientific and Technical Information (OSTI.GOV)
Langlois, R G; Brown, S; Burris, L
An early warning system to counter bioterrorism, the Autonomous Pathogen Detection System (APDS) continuously monitors the environment for the presence of biological pathogens (e.g., anthrax) and once detected, it sounds an alarm much like a smoke detector warns of a fire. Long before September 11, 2001, this system was being developed to protect domestic venues and events including performing arts centers, mass transit systems, major sporting and entertainment events, and other high profile situations in which the public is at risk of becoming a target of bioterrorist attacks. Customizing off-the-shelf components and developing new components, a multidisciplinary team developed APDS,more » a stand-alone system for rapid, continuous monitoring of multiple airborne biological threat agents in the environment. The completely automated APDS samples the air, prepares fluid samples in-line, and performs two orthogonal tests: immunoassay and nucleic acid detection. When compared to competing technologies, APDS is unprecedented in terms of flexibility and system performance.« less
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Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency
Carpier, Jean-Marie; Lucas, Carrie L.
2018-01-01
Activated PI3Kδ Syndrome (APDS) is an inherited immune disorder caused by heterozygous, gain-of-function mutations in the genes encoding the phosphoinositide 3-kinase delta (PI3Kδ) subunits p110δ or p85δ. This recently described primary immunodeficiency disease (PID) is characterized by recurrent sinopulmonary infections, lymphoproliferation, and susceptibility to herpesviruses, with Epstein–Barr virus (EBV) infection being most notable. A broad range of PIDs having disparate, molecularly defined genetic etiology can cause susceptibility to EBV, lymphoproliferative disease, and lymphoma. Historically, PID patients with loss-of-function mutations causing defective cell-mediated cytotoxicity or antigen receptor signaling were found to be highly susceptible to pathological EBV infection. By contrast, the gain of function in PI3K signaling observed in APDS patients paradoxically renders these patients susceptible to EBV, though the underlying mechanisms are incompletely understood. At a cellular level, APDS patients exhibit deranged B lymphocyte development and defects in class switch recombination, which generally lead to defective immunoglobulin production. Moreover, APDS patients also demonstrate an abnormal skewing of T cells toward terminal effectors with short telomeres and senescence markers. Here, we review APDS with a particular focus on how the altered lymphocyte biology in these patients may confer EBV susceptibility. PMID:29387064
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Le Corff, Yann; Toupin, Jean
2014-12-01
Studies have shown strong continuity between conduct disorder (CD) in adolescence and antisocial personality disorder (APD) in adulthood. Researchers have been trying to explain why some adolescents with CD persist into adult APD and others do not. A few studies reported that overt and covert CD symptoms have a differential predictive power for APD, with mixed results. The present study aimed to evaluate the prospective association of overt and covert CD symptoms with APD in a sample of male adolescents with CD (N = 128, mean age = 15.6, SD = 1.6). Participants were recruited at intake in Quebec Youth Centers and reassessed 3 years later (n = 73). CD and ADHD symptoms were assessed at intake with the DISC-R while APD was assessed 3 years later with the SCID-II. Logistic regression results showed that, contrary to previous prospective studies (Lahey, Loeber, Burke, & Applegate, 2005; Washburn et al., 2007), overt (OR = 2.12, 95% CI [1.29, 3.50]) but not covert (OR = 1.04, 95% CI [0.69, 1.56]) symptoms predicted later APD, controlling for ADHD symptoms and socioeconomic status. It is hypothesized that the divergence with previous studies may be explained by the higher mean number and wider range of overt CD symptoms in our sample.
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Luquin, Maria-Rosario; Kulisevsky, Jaime; Martinez-Martin, Pablo; Mir, Pablo; Tolosa, Eduardo S
2017-01-01
To date, no consensus exists on the key factors for diagnosing advanced Parkinson disease (APD). To obtain consensus on the definition of APD, we performed a prospective, multicenter, Spanish nationwide, 3-round Delphi study (CEPA study). An ad hoc questionnaire was designed with 33 questions concerning the relevance of several clinical features for APD diagnosis. In the first-round, 240 neurologists of the Spanish Movement Disorders Group participated in the study. The results obtained were incorporated into the questionnaire and both, results and questionnaire, were sent out to and fulfilled by 26 experts in Movement Disorders. Review of results from the second-round led to a classification of symptoms as indicative of "definitive," "probable," and "possible" APD. This classification was confirmed by 149 previous participating neurologists in a third-round, where 92% completely or very much agreed with the classification. Definitive symptoms of APD included disability requiring help for the activities of daily living, presence of motor fluctuations with limitations to perform basic activities of daily living without help, severe dysphagia, recurrent falls, and dementia. These results will help neurologists to identify some key factors in APD diagnosis, thus allowing users to categorize the patients for a homogeneous recognition of this condition.
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NASA Astrophysics Data System (ADS)
Kholodnov, Viacheslav; Drugova, Albina; Nikitin, Mikhail; Chekanova, Galina
2012-10-01
Technology of infrared (IR) avalanche photodiodes (APDs) gradually moves from simple single element APD to 2D focal plane arrays (FPA). Spectral covering of APDs is expanded continuously from classic 1.3 μm to longer wavelengths due to using of narrow-gap semiconductor materials like Hg1-xCdxTe. APDs are of great interest to developers and manufacturers of different optical communication, measuring and 3D reconstruction thermal imaging systems. Major IR detector materials for manufacturing of high-performance APDs became heteroepitaxial structures InxGa1-xAsyP1-y and Hg1-xCdxTe. Progress in IR APD technology was achieved through serious improvement in material growing techniques enabling forming of multilayer heterostuctures with separate absorption and multiplication regions (SAM). Today SAM-APD design can be implemented both on InxGa1-xAsyP1-y and Hg1-xCdxTe multilayer heteroepitaxial structures. To create the best performance optimal design avalanche heterophotodiode (AHPD) it is necessary to carry out a detailed theoretical analysis of basic features of generation, avalanche breakdown and multiplication of charge carriers in proper heterostructure. Optimization of AHPD properties requires comprehensive estimation of AHPD's pixel performance depending on pixel's multi-layer structure design, layers doping, distribution of electric field in the structure and operating temperature. Objective of the present article is to compare some features of 1.55 μm SAM-AHPDs based on InxGa1-xAsyP1-y and Hg1-xCdxTe.
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Hyde, Luke W; Byrd, Amy L; Votruba-Drzal, Elizabeth; Hariri, Ahmad R; Manuck, Stephen B
2014-02-01
Previous studies have emphasized that antisocial personality disorder (APD) and psychopathy overlap highly but differ critically in several features, notably negative emotionality (NEM) and possibly amygdala reactivity to social signals of threat and distress. Here we examined whether dimensions of psychopathy and APD correlate differentially with NEM and amygdala reactivity to emotional faces. Testing these relationships among healthy individuals, dimensions of psychopathy and APD were generated by the profile matching technique of Lynam and Widiger (2001), using facet scales of the NEO Personality Inventory-Revised, and amygdala reactivity was measured using a well-established emotional faces task, in a community sample of 103 men and women. Higher psychopathy scores were associated with lower NEM and lower amygdala reactivity, whereas higher APD scores were related to greater NEM and greater amygdala reactivity, but only after overlapping variance in APD and psychopathy was adjusted for in the statistical model. Amygdala reactivity did not mediate the relationship of APD and psychopathy scores to NEM. Supplemental analyses also compared other measures of factors within psychopathy in predicting NEM and amygdala reactivity and found that Factor 2 psychopathy was positively related to NEM and amygdala reactivity across measures of psychopathy. The overall findings replicate seminal observations on NEM in psychopathy by Hicks and Patrick (2006) and extend this work to neuroimaging in a normative population. They also suggest that one critical way in which APD and psychopathy dimensions may differ in their etiology is through their opposing levels of NEM and amygdala reactivity to threat. PsycINFO Database Record (c) 2014 APA, all rights reserved.
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Hyde, Luke W.; Byrd, Amy L.; Votruba-Drzal, Elizabeth; Hariri, Ahmad R.; Manuck, Stephen B.
2014-01-01
Previous studies have emphasized that antisocial personality disorder (APD) and psychopathy overlap highly but differ critically in several features, notably negative emotionality (NEM) and possibly amygdala reactivity to social signals of threat and distress. Here we examined whether dimensions of psychopathy and APD correlate differentially with NEM and amygdala reactivity to emotional faces. Testing these relationships among healthy individuals, dimensions of psychopathy and APD were generated by the profile matching technique of Lynam and Widiger (2001), using facet scales of the NEO Personality Inventory-Revised, and amygdala reactivity was measured using a well-established emotional faces task, in a community sample of 103 men and women. Higher psychopathy scores were associated with lower NEM and lower amygdala reactivity, whereas higher APD scores were related to greater NEM and greater amygdala reactivity, but only after overlapping variance in APD and psychopathy was adjusted for in the statistical model. Amygdala reactivity did not mediate the relationship of APD and psychopathy scores to NEM. Supplemental analyses also compared other measures of factors within psychopathy in predicting NEM and amygdala reactivity and found that Factor 2 psychopathy was positively related to NEM and amygdala reactivity across measures of psychopathy. The overall findings replicate seminal observations on NEM in psychopathy by Hicks and Patrick (2006) and extend this work to neuroimaging in a normative population. They also suggest that one critical way in which APD and psychopathy dimensions may differ in their etiology is through their opposing levels of NEM and amygdala reactivity to threat. PMID:24661171
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Meltzer, H Y; Matsubara, S; Lee, J C
1989-10-01
The pKi values of 13 reference typical and 7 reference atypical antipsychotic drugs (APDs) for rat striatal dopamine D-1 and D-2 receptor binding sites and cortical serotonin (5-HT2) receptor binding sites were determined. The atypical antipsychotics had significantly lower pKi values for the D-2 but not 5-HT2 binding sites. There was a trend for a lower pKi value for the D-1 binding site for the atypical APD. The 5-HT2 and D-1 pKi values were correlated for the typical APD whereas the 5-HT2 and D-2 pKi values were correlated for the atypical APD. A stepwise discriminant function analysis to determine the independent contribution of each pKi value for a given binding site to the classification as a typical or atypical APD entered the D-2 pKi value first, followed by the 5-HT2 pKi value. The D-1 pKi value was not entered. A discriminant function analysis correctly classified 19 of 20 of these compounds plus 14 of 17 additional test compounds as typical or atypical APD for an overall correct classification rate of 89.2%. The major contributors to the discriminant function were the D-2 and 5-HT2 pKi values. A cluster analysis based only on the 5-HT2/D2 ratio grouped 15 of 17 atypical + one typical APD in one cluster and 19 of 20 typical + two atypical APDs in a second cluster, for an overall correct classification rate of 91.9%. When the stepwise discriminant function was repeated for all 37 compounds, only the D-2 and 5-HT2 pKi values were entered into the discriminant function.(ABSTRACT TRUNCATED AT 250 WORDS)
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Chemical agent simulant release from clothing following vapor exposure.
Feldman, Robert J
2010-02-01
Most ambulatory victims of a terrorist chemical attack will have exposure to vapor only. The study objective was to measure the duration of chemical vapor release from various types of clothing. A chemical agent was simulated using methyl salicylate (MeS), which has similar physical properties to sulfur mustard and was the agent used in the U.S. Army's Man-In-Simulant Test (MIST). Vapor concentration was measured with a Smiths Detection Advanced Portable Detector (APD)-2000 unit. The clothing items were exposed to vapor for 1 hour in a sealed cabinet; vapor concentration was measured at the start and end of each exposure. Clothing was then removed and assessed every 5 minutes with the APD-2000, using a uniform sweep pattern, until readings remained 0. Concentration and duration of vapor release from clothing varied with clothing composition and construction. Lightweight cotton shirts and jeans had the least trapped vapor; down outerwear, the most. Vapor concentration near the clothing often increased for several minutes after the clothing was removed from the contaminated environment. Compression of thick outerwear released additional vapor. Mean times to reach 0 ranged from 7 minutes for jeans to 42 minutes for down jackets. This simulation model of chemical vapor release demonstrates persistent presence of simulant vapor over time. This implies that chemical vapor may be released from the victims' clothing after they are evacuated from the site of exposure, resulting in additional exposure of victims and emergency responders. Insulated outerwear can release additional vapor when handled. If a patient has just moved to a vapor screening point, immediate assessment before additional vapor can be released from the clothing can lead to a false-negative assessment of contamination.
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Equivalent circuit model of Ge/Si separate absorption charge multiplication avalanche photodiode
NASA Astrophysics Data System (ADS)
Wang, Wei; Chen, Ting; Yan, Linshu; Bao, Xiaoyuan; Xu, Yuanyuan; Wang, Guang; Wang, Guanyu; Yuan, Jun; Li, Junfeng
2018-03-01
The equivalent circuit model of Ge/Si Separate Absorption Charge Multiplication Avalanche Photodiode (SACM-APD) is proposed. Starting from the carrier rate equations in different regions of device and considering the influences of non-uniform electric field, noise, parasitic effect and some other factors, the equivalent circuit model of SACM-APD device is established, in which the steady-state and transient current voltage characteristics can be described exactly. In addition, the proposed Ge/Si SACM APD equivalent circuit model is embedded in PSpice simulator. The important characteristics of Ge/Si SACM APD such as dark current, frequency response, shot noise are simulated, the simulation results show that the simulation with the proposed model are in good agreement with the experimental results.
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NASA Astrophysics Data System (ADS)
Lee, Min Soo; Park, Byung Kwon; Woo, Min Ki; Park, Chang Hoon; Kim, Yong-Su; Han, Sang-Wook; Moon, Sung
2016-12-01
We developed a countermeasure against blinding attacks on low-noise detectors with a background-noise-cancellation scheme in quantum key distribution (QKD) systems. Background-noise cancellation includes self-differencing and balanced avalanche photon diode (APD) schemes and is considered a promising solution for low-noise APDs, which are critical components in high-performance QKD systems. However, its vulnerability to blinding attacks has been recently reported. In this work, we propose a countermeasure that prevents this potential security loophole from being used in detector blinding attacks. An experimental QKD setup is implemented and various tests are conducted to verify the feasibility and performance of the proposed method. The obtained measurement results show that the proposed scheme successfully detects occurring blinding-attack-based hacking attempts.
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An integrated fluorescence detection system in poly(dimethylsiloxane) for microfluidic applications.
Chabinyc, M L; Chiu, D T; McDonald, J C; Stroock, A D; Christian, J F; Karger, A M; Whitesides, G M
2001-09-15
This paper describes a prototype of an integrated fluorescence detection system that uses a microavalanche photodiode (microAPD) as the photodetector for microfluidic devices fabricated in poly(dimethylsiloxane) (PDMS). The prototype device consisted of a reusable detection system and a disposable microfluidic system that was fabricated using rapid prototyping. The first step of the procedure was the fabrication of microfluidic channels in PDMS and the encapsulation of a multimode optical fiber (100-microm core diameter) in the PDMS; the tip of the fiber was placed next to the side wall of one of the channels. The optical fiber was used to couple light into the microchannel for the excitation of fluorescent analytes. The photodetector, a prototype solid-state microAPD array, was embedded in a thick slab (1 cm) of PDMS. A thin (80 microm) colored polycarbonate filter was placed on the top of the embedded microAPD to absorb scattered excitation light before it reached the detector. The microAPD was placed below the microchannel and orthogonal to the axis of the optical fiber. The close proximity (approximately 200 microm) of the microAPD to the microchannel made it unnecessary to incorporate transfer optics; the pixel size of the microAPD (30 microm) matched the dimensions of the channels (50 microm). A blue light-emitting diode was used for fluorescence excitation. The microAPD was operated in Geiger mode to detect the fluorescence. The detection limit of the prototype (approximately 25 nM) was determined by finding the minimum detectable concentration of a solution of fluorescein. The device was used to detect the separation of a mixture of proteins and small molecules by capillary electrophoresis; the separation illustrated the suitability of this integrated fluorescence detection system for bioanalytical applications.
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Enhanced effect of VEGF165 on L-type calcium currents in guinea-pig cardiac ventricular myocytes.
Xing, Wenlu; Gao, Chuanyu; Qi, Datun; Zhang, You; Hao, Peiyuan; Dai, Guoyou; Yan, Ganxin
2017-01-01
The mechanisms of vascular endothelial growth factor 165 (VEGF165) on electrical properties of cardiomyocytes have not been fully elucidated. The aim of this study is to test the hypothesis that VEGF165, an angiogenesis-initiating factor, affects L-type calcium currents (I Ca,L ) and cell membrane potential in cardiac myocytes by acting on VEGF type-2 receptors (VEGFR2). I Ca,L and action potentials (AP) were recorded by the whole-cell patch clamp method in isolated guinea-pig ventricular myocytes treated with different concentrations of VEGF165 proteins. Using a VEGFR2 inhibitor, we also tested the receptor of VEGF165 in cardiomyocytes. We found that VEGF165 increased I Ca,L in a concentration-dependent manner. SU5416, a VEGFR2 inhibitor, almost completely eliminated VEGF165-induced I Ca,L increase. VEGF165 had no significant influence on action potential 90 (APD90) and other properties of AP. We conclude that in guinea-pig ventricular myocytes, I Ca,L can be increased by VEGF165 in a concentration-dependent manner through binding to VEGFR2 without causing any significant alteration to action potential duration. Results of this study may further expound the safety of VEGF165 when used in the intervention of heart diseases. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
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Large Diameter, High Speed InGaAs Receivers for Free-Space Lasercom
2007-01-01
appropriate transimpedance amplifier and limiting amplifier . Development and testing of the APD receivers will be described below. 15. SUBJECT TERMS 16...available transimpedance amplifiers (TIA) from Maxim of Dallas. There have also been several devices built in house by NRL in 8-pin TO-39 headers...manufacture a large area, high speed InGaAs APD with an effective ionization ratio of < 0.2 and by matching the APD device with an appropriate transimpedance
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Development of a 32-channel ASIC for an X-ray APD detector onboard the ISS
NASA Astrophysics Data System (ADS)
Arimoto, Makoto; Harita, Shohei; Sugita, Satoshi; Yatsu, Yoichi; Kawai, Nobuyuki; Ikeda, Hirokazu; Tomida, Hiroshi; Isobe, Naoki; Ueno, Shiro; Mihara, Tatehiro; Serino, Motoko; Kohmura, Takayoshi; Sakamoto, Takanori; Yoshida, Atsumasa; Tsunemi, Hiroshi; Hatori, Satoshi; Kume, Kyo; Hasegawa, Takashi
2018-02-01
We report on the design and performance of a mixed-signal application specific integrated circuit (ASIC) dedicated to avalanche photodiodes (APDs) in order to detect hard X-ray emissions in a wide energy band onboard the International Space Station. To realize wide-band detection from 20 keV to 1 MeV, we use Ce:GAGG scintillators, each coupled to an APD, with low-noise front-end electronics capable of achieving a minimum energy detection threshold of 20 keV. The developed ASIC has the ability to read out 32-channel APD signals using 0.35 μm CMOS technology, and an analog amplifier at the input stage is designed to suppress the capacitive noise primarily arising from the large detector capacitance of the APDs. The ASIC achieves a performance of 2099 e- + 1.5 e-/pF at root mean square (RMS) with a wide 300 fC dynamic range. Coupling a reverse-type APD with a Ce:GAGG scintillator, we obtain an energy resolution of 6.7% (FWHM) at 662 keV and a minimum detectable energy of 20 keV at room temperature (20 °C). Furthermore, we examine the radiation tolerance for space applications by using a 90 MeV proton beam, confirming that the ASIC is free of single-event effects and can operate properly without serious degradation in analog and digital processing.
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Lotfi, Yones; Mehrkian, Saiedeh; Moossavi, Abdollah; Zadeh, Soghrat Faghih; Sadjedi, Hamed
2016-03-01
This study assessed the relationship between working memory capacity and auditory stream segregation by using the concurrent minimum audible angle in children with a diagnosed auditory processing disorder (APD). The participants in this cross-sectional, comparative study were 20 typically developing children and 15 children with a diagnosed APD (age, 9-11 years) according to the subtests of multiple-processing auditory assessment. Auditory stream segregation was investigated using the concurrent minimum audible angle. Working memory capacity was evaluated using the non-word repetition and forward and backward digit span tasks. Nonparametric statistics were utilized to compare the between-group differences. The Pearson correlation was employed to measure the degree of association between working memory capacity and the localization tests between the 2 groups. The group with APD had significantly lower scores than did the typically developing subjects in auditory stream segregation and working memory capacity. There were significant negative correlations between working memory capacity and the concurrent minimum audible angle in the most frontal reference location (0° azimuth) and lower negative correlations in the most lateral reference location (60° azimuth) in the children with APD. The study revealed a relationship between working memory capacity and auditory stream segregation in children with APD. The research suggests that lower working memory capacity in children with APD may be the possible cause of the inability to segregate and group incoming information.
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Vaiani, Elisa; Malossetti, Carmen; Vega, Lina Margarita; Zubizarreta, Pedro; Braier, Jorge; Belgorosky, Alicia
2017-01-01
Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder of unknown etiopathogenesis. Central diabetes insipidus (CDI) is the most frequent endocrine manifestation and is a known risk factor for the development of further anterior pituitary hormone deficiencies (APD). However, not all CDI patients develop APD, as observed during prolonged periods of follow-up. To find predictors of developing APD in LCH children with CDI followed in our institution. We retrospectively analysed 44 patients over a median period (quartiles) of 12.3 years (8.79-14.24). Patients were subdivided into group 1 and group 2, according to absence or presence of APD, respectively. The main variables studied were: (1) chronological age (CA) at LCH diagnosis, (2) the primary site of LCH at diagnosis: low risk (LR) and multisystemic risk organs, and (3) the presence of reactivation. Multivariate Cox regression analysis showed that APD was positively associated with CA at LCH diagnosis [relative risk (RR) 1.14, p < 0.01], the LR clinical form (RR 8.6, p < 0.03), and negatively associated with the presence of reactivations (RR 0.3, p < 0.01). Patients with older CA at LCH diagnosis, LR clinical forms, and fewer reactivation episodes might represent a subgroup of paediatric LCH CDI patients with a higher risk of developing APD. © 2016 S. Karger AG, Basel.
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Luby, Stephen P; Halder, Amal K; Islam, Khairul; Opel, Aftab; Shoab, Abul K; Ghosh, Probir K; Rahman, Mahbubur; Mahon, Therese; Unicomb, Leanne
2017-01-01
Background Many adolescent girls in low-income and middle-income countries lack appropriate facilities and support in school to manage menstruation. Little research has been conducted on how menstruation affects school absence. This study examines the association of menstrual hygiene management knowledge, facilities and practice with absence from school during menstruation among Bangladeshi schoolgirls. Methods We conducted a nationally representative, cross-sectional study in Bangladeshi schools from March to June 2013 among girls 11 to 17 years old who reached menarche. We sampled 700 schools from 50 urban and 50 rural clusters using a probability proportional to size technique. We interviewed 2332 schoolgirls and conducted spot checks in each school for menstrual hygiene facilities. To assess factors associated with reported school absence, we estimated adjusted prevalence difference (APD) for controlling confounders’ effect using generalised estimating equations to account for school-level clustering. Results Among schoolgirls who reached menarche, 41% (931) reported missing school, an average of 2.8 missed days per menstrual cycle. Students who felt uncomfortable at school during menstruation (99% vs 32%; APD=58%; CI 54 to 63) and who believed menstrual problems interfere with school performance (64% vs 30%; APD=27; CI 20 to 33) were more likely to miss school during menstruation than those who did not. School absence during menstruation was less common among girls attending schools with unlocked toilet for girls (35% vs 43%; APD=−5.4; CI −10 to –1.6). School absence was more common among girls who were forbidden from any activities during menstruation (41% vs 33%; APD=9.1; CI 3.3 to 14). Conclusion Risk factors for school absence included girl’s attitude, misconceptions about menstruation, insufficient and inadequate facilities at school, and family restriction. Enabling girls to manage menstruation at school by providing knowledge and management methods prior to menarche, privacy and a positive social environment around menstrual issues has the potential to benefit students by reducing school absence. PMID:28694347
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Alam, Mahbub-Ul; Luby, Stephen P; Halder, Amal K; Islam, Khairul; Opel, Aftab; Shoab, Abul K; Ghosh, Probir K; Rahman, Mahbubur; Mahon, Therese; Unicomb, Leanne
2017-07-09
Many adolescent girls in low-income and middle-income countries lack appropriate facilities and support in school to manage menstruation. Little research has been conducted on how menstruation affects school absence. This study examines the association of menstrual hygiene management knowledge, facilities and practice with absence from school during menstruation among Bangladeshi schoolgirls. We conducted a nationally representative, cross-sectional study in Bangladeshi schools from March to June 2013 among girls 11 to 17 years old who reached menarche. We sampled 700 schools from 50 urban and 50 rural clusters using a probability proportional to size technique. We interviewed 2332 schoolgirls and conducted spot checks in each school for menstrual hygiene facilities. To assess factors associated with reported school absence, we estimated adjusted prevalence difference (APD) for controlling confounders' effect using generalised estimating equations to account for school-level clustering. Among schoolgirls who reached menarche, 41% (931) reported missing school, an average of 2.8 missed days per menstrual cycle. Students who felt uncomfortable at school during menstruation (99% vs 32%; APD=58%; CI 54 to 63) and who believed menstrual problems interfere with school performance (64% vs 30%; APD=27; CI 20 to 33) were more likely to miss school during menstruation than those who did not. School absence during menstruation was less common among girls attending schools with unlocked toilet for girls (35% vs 43%; APD=-5.4; CI -10 to -1.6). School absence was more common among girls who were forbidden from any activities during menstruation (41% vs 33%; APD=9.1; CI 3.3 to 14). Risk factors for school absence included girl's attitude, misconceptions about menstruation, insufficient and inadequate facilities at school, and family restriction. Enabling girls to manage menstruation at school by providing knowledge and management methods prior to menarche, privacy and a positive social environment around menstrual issues has the potential to benefit students by reducing school absence. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Cacace, Anthony T; McFarland, Dennis J
2013-01-01
Tests of auditory perception, such as those used in the assessment of central auditory processing disorders ([C]APDs), represent a domain in audiological assessment where measurement of this theoretical construct is often confounded by nonauditory abilities due to methodological shortcomings. These confounds include the effects of cognitive variables such as memory and attention and suboptimal testing paradigms, including the use of verbal reproduction as a form of response selection. We argue that these factors need to be controlled more carefully and/or modified so that their impact on tests of auditory and visual perception is only minimal. To advocate for a stronger theoretical framework than currently exists and to suggest better methodological strategies to improve assessment of auditory processing disorders (APDs). Emphasis is placed on adaptive forced-choice psychophysical methods and the use of matched tasks in multiple sensory modalities to achieve these goals. Together, this approach has potential to improve the construct validity of the diagnosis, enhance and develop theory, and evolve into a preferred method of testing. Examination of methods commonly used in studies of APDs. Where possible, currently used methodology is compared to contemporary psychophysical methods that emphasize computer-controlled forced-choice paradigms. In many cases, the procedures used in studies of APD introduce confounding factors that could be minimized if computer-controlled forced-choice psychophysical methods were utilized. Ambiguities of interpretation, indeterminate diagnoses, and unwanted confounds can be avoided by minimizing memory and attentional demands on the input end and precluding the use of response-selection strategies that use complex motor processes on the output end. Advocated are the use of computer-controlled forced-choice psychophysical paradigms in combination with matched tasks in multiple sensory modalities to enhance the prospect of obtaining a valid diagnosis. American Academy of Audiology.
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Haasum, Ylva; Fastbom, Johan; Johnell, Kristina
2016-06-01
It has been suggested that depression in Parkinson's Disease (PD) is often unrecognized and undertreated. However, few previous studies have studied the use of antidepressants in a large sample of both home-dwelling and institutionalized elderly persons with PD. We aimed to study the use of antidepressants in older persons using anti-parkinson drugs (APD, used as a proxy for PD), stratified by residential setting. We analyzed individual data on age, sex, residential setting and drug use in over 1.5 million older persons in the Swedish Prescribed Drug Register on 31th of December 2013. Twenty-two percent of the home-dwellers and 50% of the institutionalized elderly persons with APD used antidepressants. Persons with APD had a higher probability of use of any antidepressant compared to persons without APD. A selective serotonin reuptake inhibitor (SSRI) was the most commonly used antidepressants in both settings followed by mirtazapin. The high use of antidepressants among older persons with APD warrants further studies on the quality of treatment of depression in PD. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Geiger mode avalanche photodiodes for microarray systems
NASA Astrophysics Data System (ADS)
Phelan, Don; Jackson, Carl; Redfern, R. Michael; Morrison, Alan P.; Mathewson, Alan
2002-06-01
New Geiger Mode Avalanche Photodiodes (GM-APD) have been designed and characterized specifically for use in microarray systems. Critical parameters such as excess reverse bias voltage, hold-off time and optimum operating temperature have been experimentally determined for these photon-counting devices. The photon detection probability, dark count rate and afterpulsing probability have been measured under different operating conditions. An active- quench circuit (AQC) is presented for operating these GM- APDs. This circuit is relatively simple, robust and has such benefits as reducing average power dissipation and afterpulsing. Arrays of these GM-APDs have already been designed and together with AQCs open up the possibility of having a solid-state microarray detector that enables parallel analysis on a single chip. Another advantage of these GM-APDs over current technology is their low voltage CMOS compatibility which could allow for the fabrication of an AQC on the same device. Small are detectors have already been employed in the time-resolved detection of fluorescence from labeled proteins. It is envisaged that operating these new GM-APDs with this active-quench circuit will have numerous applications for the detection of fluorescence in microarray systems.
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Rota-Donahue, Christine; Schwartz, Richard G.; Shafer, Valerie; Sussman, Elyse S.
2016-01-01
Background Frequency discrimination is often impaired in children developing language atypically. However, findings in the detection of small frequency changes in these children are conflicting. Previous studies on children’s auditory perceptual abilities usually involved establishing differential sensitivity thresholds in sample populations who were not tested for auditory deficits. To date, there are no data comparing suprathreshold frequency discrimination ability in children tested for both auditory processing and language skills. Purpose This study examined the perception of small frequency differences (Δf) in children with auditory processing disorder (APD) and/or specific language impairment (SLI). The aim was to determine whether children with APD and children with SLI showed differences in their behavioral responses to frequency changes. Results were expected to identify different degrees of impairment and shed some light on the auditory perceptual overlap between pediatric APD and SLI. Research Design An experimental group design using a two-alternative forced-choice procedure was used to determine frequency discrimination ability for three magnitudes of Δf from the 1000-Hz base frequency. Study Sample Thirty children between 10 years of age and 12 years, 11 months of age: 17 children with APD and/or SLI, and 13 typically developing (TD) peers participated. The clinical groups included four children with APD only, four children with SLI only, and nine children with both APD and SLI. Data Collection and Analysis Behavioral data collected using headphone delivery were analyzed using the sensitivity index d′, calculated for three Δf was 2%, 5%, and 15% of the base frequency or 20, 50, and 150 Hz. Correlations between the dependent variable d′ and the independent variables measuring auditory processing and language skills were also obtained. A stepwise regression analysis was then performed. Results TD children and children with APD and/or SLI differed in the detection of small-tone Δf. In addition, APD or SLI status affected behavioral results differently. Comparisons between auditory processing test scores or language test scores and the sensitivity index d′ showed different strengths of correlation based on the magnitudes of the Δf. Auditory processing scores showed stronger correlation to the sensitivity index d′ for the small Δf, while language scores showed stronger correlation to the sensitivity index d′ for the large Δf. Conclusion Although children with APD and/or SLI have difficulty with behavioral frequency discrimination, this difficulty may stem from two different levels: a basic auditory level for children with APD and a higher language processing level for children with SLI; the frequency discrimination performance seemed to be affected by the labeling demands of the same versus different frequency discrimination task for the children with SLI. PMID:27310407
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Rota-Donahue, Christine; Schwartz, Richard G; Shafer, Valerie; Sussman, Elyse S
2016-06-01
Frequency discrimination is often impaired in children developing language atypically. However, findings in the detection of small frequency changes in these children are conflicting. Previous studies on children's auditory perceptual abilities usually involved establishing differential sensitivity thresholds in sample populations who were not tested for auditory deficits. To date, there are no data comparing suprathreshold frequency discrimination ability in children tested for both auditory processing and language skills. : This study examined the perception of small frequency differences (∆ƒ) in children with auditory processing disorder (APD) and/or specific language impairment (SLI). The aim was to determine whether children with APD and children with SLI showed differences in their behavioral responses to frequency changes. Results were expected to identify different degrees of impairment and shed some light on the auditory perceptual overlap between pediatric APD and SLI. An experimental group design using a two-alternative forced-choice procedure was used to determine frequency discrimination ability for three magnitudes of ∆ƒ from the 1000-Hz base frequency. Thirty children between 10 years of age and 12 years, 11 months of age: 17 children with APD and/or SLI, and 13 typically developing (TD) peers participated. The clinical groups included four children with APD only, four children with SLI only, and nine children with both APD and SLI. Behavioral data collected using headphone delivery were analyzed using the sensitivity index d', calculated for three ∆ƒ was 2%, 5%, and 15% of the base frequency or 20, 50, and 150 Hz. Correlations between the dependent variable d' and the independent variables measuring auditory processing and language skills were also obtained. A stepwise regression analysis was then performed. TD children and children with APD and/or SLI differed in the detection of small-tone ∆ƒ. In addition, APD or SLI status affected behavioral results differently. Comparisons between auditory processing test scores or language test scores and the sensitivity index d' showed different strengths of correlation based on the magnitudes of the ∆ƒ. Auditory processing scores showed stronger correlation to the sensitivity index d' for the small ∆ƒ, while language scores showed stronger correlation to the sensitivity index d' for the large ∆ƒ. Although children with APD and/or SLI have difficulty with behavioral frequency discrimination, this difficulty may stem from two different levels: a basic auditory level for children with APD and a higher language processing level for children with SLI; the frequency discrimination performance seemed to be affected by the labeling demands of the same versus different frequency discrimination task for the children with SLI. American Academy of Audiology.
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Experimental evaluation of penetration capabilities of a Geiger-mode APD array laser radar system
NASA Astrophysics Data System (ADS)
Jonsson, Per; Tulldahl, Michael; Hedborg, Julia; Henriksson, Markus; Sjöqvist, Lars
2017-10-01
Laser radar 3D imaging has the potential to improve target recognition in many scenarios. One case that is challenging for most optical sensors is to recognize targets hidden in vegetation or behind camouflage. The range resolution of timeof- flight 3D sensors allows segmentation of obscuration and target if the surfaces are separated far enough so that they can be resolved as two distances. Systems based on time-correlated single-photon counting (TCSPC) have the potential to resolve surfaces closer to each other compared to laser radar systems based on proportional mode detection technologies and is therefore especially interesting. Photon counting detection is commonly performed with Geigermode Avalanche Photodiodes (GmAPD) that have the disadvantage that they can only detect one photon per laser pulse per pixel. A strong return from an obscuring object may saturate the detector and thus limit the possibility to detect the hidden target even if photons from the target reach the detector. The operational range where good foliage penetration is observed is therefore relatively narrow for GmAPD systems. In this paper we investigate the penetration capability through semi-transparent surfaces for a laser radar with a 128×32 pixel GmAPD array and a 1542 nm wavelength laser operating at a pulse repetition frequency of 90 kHz. In the evaluation a screen was placed behind different canvases with varying transmissions and the detected signals from the surfaces for different laser intensities were measured. The maximum return from the second surface occurs when the total detection probability is around 0.65-0.75 per pulse. At higher laser excitation power the signal from the second surface decreases. To optimize the foliage penetration capability it is thus necessary to adaptively control the laser power to keep the returned signal within this region. In addition to the experimental results, simulations to study the influence of the pulse energy on penetration through foliage in a scene with targets behind vegetation are presented. The optimum detection of targets occurs here at a slightly higher total photon count rate probability because a number of pixel have no obscuration in front the target in their field of view.
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Geiger-Mode Avalanche Photodiode Arrays Integrated to All-Digital CMOS Circuits
2016-01-20
Figure 7 4×4 GMAPD array wire bonded to CMOS timing circuits Figure 8 Low‐fill‐factor APD design used in lidar sensors The APD doping...epitaxial growth and the pixels are isolated by mesa etch. 128×32 lidar image sensors were built by bump bonding the APD arrays to a CMOS timing...passive image sensor with this large a format based on hybridization of a GMAPD array to a CMOS readout. Fig. 14 shows one of the first images taken
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Autoimmune progesterone dermatitis.
Detrixhe, A; Nikkels, A F; Dezfoulian, B
2017-11-01
Autoimmune progesterone dermatitis (APD) is an exceptional condition affecting young women of childbearing age with a high prevalence during the third decade of life. The diagnosis should be confirmed using an intradermal skin test to progesterone, during the follicular phase of the menstrual cycle. APD represents an early manifestation of autoimmune disease. A case of APD is presented who after curative treatment did not develop other autoimmune diseases during a 6-year follow-up. Dermatologists, gynecologists and obstetricians should be aware of this rare but highly invalidating entity.
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Trevitt, Sara; Simpson, Sue; Wood, Annette
2016-05-01
Closed-loop artificial pancreas device (APD) systems are externally worn medical devices that are being developed to enable people with type 1 diabetes to regulate their blood glucose levels in a more automated way. The innovative concept of this emerging technology is that hands-free, continuous, glycemic control can be achieved by using digital communication technology and advanced computer algorithms. A horizon scanning review of this field was conducted using online sources of intelligence to identify systems in development. The systems were classified into subtypes according to their level of automation, the hormonal and glycemic control approaches used, and their research setting. Eighteen closed-loop APD systems were identified. All were being tested in clinical trials prior to potential commercialization. Six were being studied in the home setting, 5 in outpatient settings, and 7 in inpatient settings. It is estimated that 2 systems may become commercially available in the EU by the end of 2016, 1 during 2017, and 2 more in 2018. There are around 18 closed-loop APD systems progressing through early stages of clinical development. Only a few of these are currently in phase 3 trials and in settings that replicate real life. © 2015 Diabetes Technology Society.
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Niles, Dana E.; Nishisaki, Akira; Sutton, Robert M.; Nysæther, Jon; Eilevstjønn, Joar; Leffelman, Jessica; Maltese, Matthew R.; Arbogast, Kristy B.; Abella, Benjamin S.; Helfaer, Mark A.; Berg, Robert A.; Nadkarni, Vinay M.
2013-01-01
Aim Cardiopulmonary resuscitation (CPR) guidelines recommend specific chest compression (CC) target depths for children. We quantitatively describe relative anterior–posterior diameter (APD) depth, actual depth, and force of CCs during real CPR events in children. Methods CC depth and force were recorded during real CPR events in children ≥8 years using FDA-approved CC sensor. Patient chest APD was measured at conclusion of each CPR event. CC data was stratified and analyzed according to age (pre-puberty, 8–14 years; post-puberty, 15+ years). Relative (% APD) and actual CC depth, corrected for mattress deflection, were assessed and compared with American Heart Association (AHA) 2005 and 2010 pediatric CPR guidelines. Results 35 events in 32 subjects included 16,158 CCs for data analysis: 16 pre-puberty (CCs = 7484, age 11.9 ± 2 years, APD 164.6 ± 25.1 mm); 19 post-puberty (CCs = 8674, age 18.0 ± 2.7 years, APD 196.5 ± 30.4 mm). After correction for mattress deflection, 92% of CC delivered to pre-puberty were <1/3 relative APD and 60% of CC were <38 mm actual depth. Mean actual CC depth (36.2 ± 9.6 mm vs. 36.8 ± 9.9 mm, p = 0.64), mean relative APD (22.5% ± 7.0% vs. 19.5 ± 6.7%, p = 0.13), and mean CC force (30.7 ± 7.6 kg vs. 33.6 ± 9.4 kg, p = 0.07) were not significantly less in pre-puberty vs. post-puberty. Conclusions During in-hospital cardiac arrest of children ≥8 years, CCs delivered by resuscitation teams were frequently <1/3 relative APD and <38 mm actual depth after mattress deflection correction, below pediatric and adult target guidelines. Mean CC actual depth and force were not significantly different in pre-puberty and post-puberty. Additional investigation to determine depth of CCs to optimize hemodynamics and outcomes is needed to inform future CPR guidelines. PMID:22079410
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Arora, S; Yadav, P; Kumar, M; Singh, S Kumar; Sureka, S Kumar; Mittal, V; Ansari, M S
2015-10-01
Disagreement exists over the ability of different diagnostic tests to define obstruction, indications and timing of surgery and which patients will benefit from surgical intervention in antenatal hydronephrosis (ANH) due to ureteropelvic junction obstruction (UPJO). We try to find a way to predict which patients of ANH due to UPJO will eventually need surgery during conservative management. Prospective single centre study involving 122 renal units at a referral centre in India. Patients on conservative management were followed using a standard protocol and operated for pre-defined indications defining failure of conservative management. Patients who underwent surgery were compared with the non-operated group in terms of sex, side, baseline grade of hydronephrosis, maximum anterioposterior diameter on first postnatal ultrasound and differential renal function on first renal scan. A total of 109 renal units qualified for conservative management. Of those, 23.9% required operative intervention during follow-up. Median time to failure of conservative management was 37 weeks. The median follow-up of non-operated cases was 54 months. Univariate analysis revealed that society of fetal urology (SFU) grade of hydronephrosis, anteroposterior diameter (APD), cortical thickness (CT), and pre-operative differential renal function (DRF) had a significant association with surgery (P < 0.05). Multivariate analysis revealed APD and pre-operative DRF as the only independent predictors for requiring surgery, while CT and initial SFU grade of hydronephrosis were not. Receiver operating curve analysis showed that an APD of 24.3 mm could predict the need for surgery, with a sensitivity of 73.1% and a specificity of 88.0%. APD and DRF are the predictive factors for surgery. We stop short of recommending surgery only on the basis of APD. Instead we recommend that efforts be made to improve the specificity of this criterion, or by using APD in perspective with the differential renal function. We can reduce the burden of investigations in those with APD <24 mm while those with APD >24 mm can be more comprehensively monitored. Copyright © 2015 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
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Temperature Control of Avalanche Photodiode Using Thermoelectric Cooler
NASA Technical Reports Server (NTRS)
Refaat, Tamer F.; Luck, William S., Jr.; DeYoung, Russell J.
1999-01-01
Avalanche photodiodes (APDS) are quantum optical detectors that are used for visible and near infrared optical detection applications. Although APDs are compact, rugged, and have an internal gain mechanism that is suitable for low light intensity; their responsivity, and therefore their output, is strongly dependent on the device temperature. Thermoelectric coolers (TEC) offers a suitable solution to this problem. A TEC is a solid state cooling device, which can be controlled by changing its current. TECs are compact and rugged, and they can precisely control the temperature to within 0.1 C with more than a 150 C temperature gradient between its surfaces. In this Memorandum, a proportional integral (PI) temperature controller for APDs using a TEC is discussed. The controller is compact and can successfully cool the APD to almost 0 C in an ambient temperature environment of up to 27 C.
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Characterisation of Geiger-mode avalanche photodiodes for medical imaging applications
NASA Astrophysics Data System (ADS)
Britvitch, I.; Johnson, I.; Renker, D.; Stoykov, A.; Lorenz, E.
2007-02-01
Recently developed multipixel Geiger-mode avalanche photodiodes (G-APDs) are very promising candidates for the detection of light in medical imaging instruments (e.g. positron emission tomography) as well as in high-energy physics experiments and astrophysical applications. G-APDs are especially well suited for morpho-functional imaging (multimodality PET/CT, SPECT/CT, PET/MRI, SPECT/MRI). G-APDs have many advantages compared to conventional photosensors such as photomultiplier tubes because of their compact size, low-power consumption, high quantum efficiency and insensitivity to magnetic fields. Compared to avalanche photodiodes and PIN diodes, they are advantageous because of their high gain, reduced sensitivity to pick up and the so-called nuclear counter effect and lower noise. We present measurements of the basic G-APD characteristics: photon detection efficiency, gain, inter-cell crosstalk, dynamic range, recovery time and dark count rate.
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NASA Astrophysics Data System (ADS)
Abe, Tomoki; Uchida, Shigeto; Tanaka, Keita; Fujisawa, Takanobu; Kasada, Hirofumi; Ando, Koshi; Akaiwa, Kazuaki; Ichino, Kunio
2018-05-01
We investigated device degradation in PEDOT:PSS/ZnSSe organic-inorganic hybrid ultraviolet avalanche photodiodes (UV-APDs). ZnSSe/n-GaAs wafers were grown by molecular beam epitaxy, and PEDOT:PSS window layers were formed by inkjet technique. We observed rapid degradation with APD-mode stress (˜ 30 V) in the N2 (4 N) atmosphere, while we observed no marked change in forward bias current stress and photocurrent stress. In the case of a vacuum condition, we observed no detectable degradation in the dark avalanche current with APD-mode stress. Therefore, the degradation in the PEDOT:PSS/ZnSSe interface under the APD-mode stress was caused by the residual water vapor or oxygen in the N2 atmosphere and could be controlled by vacuum packaging.
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Lotfi, Yones; Mehrkian, Saiedeh; Moossavi, Abdollah; Zadeh, Soghrat Faghih; Sadjedi, Hamed
2016-01-01
Background: This study assessed the relationship between working memory capacity and auditory stream segregation by using the concurrent minimum audible angle in children with a diagnosed auditory processing disorder (APD). Methods: The participants in this cross-sectional, comparative study were 20 typically developing children and 15 children with a diagnosed APD (age, 9–11 years) according to the subtests of multiple-processing auditory assessment. Auditory stream segregation was investigated using the concurrent minimum audible angle. Working memory capacity was evaluated using the non-word repetition and forward and backward digit span tasks. Nonparametric statistics were utilized to compare the between-group differences. The Pearson correlation was employed to measure the degree of association between working memory capacity and the localization tests between the 2 groups. Results: The group with APD had significantly lower scores than did the typically developing subjects in auditory stream segregation and working memory capacity. There were significant negative correlations between working memory capacity and the concurrent minimum audible angle in the most frontal reference location (0° azimuth) and lower negative correlations in the most lateral reference location (60° azimuth) in the children with APD. Conclusion: The study revealed a relationship between working memory capacity and auditory stream segregation in children with APD. The research suggests that lower working memory capacity in children with APD may be the possible cause of the inability to segregate and group incoming information. PMID:26989281
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NASA Astrophysics Data System (ADS)
Li, Zhenjie; Li, Qiuju; Chang, Jinfan; Ma, Yichao; Liu, Peng; Wang, Zheng; Hu, Michael Y.; Zhao, Jiyong; Alp, E. E.; Xu, Wei; Tao, Ye; Wu, Chaoqun; Zhou, Yangfan
2017-10-01
A four-channel nanosecond time-resolved avalanche-photodiode (APD) detector system is developed at Beijing Synchrotron Radiation. It uses a single module for signal processing and readout. This integrated system provides better reliability and flexibility for custom improvement. The detector system consists of three parts: (i) four APD sensors, (ii) four fast preamplifiers and (iii) a time-digital-converter (TDC) readout electronics. The C30703FH silicon APD chips fabricated by Excelitas are used as the sensors of the detectors. It has an effective light-sensitive area of 10 × 10 mm2 and an absorption layer thickness of 110 μm. A fast preamplifier with a gain of 59 dB and bandwidth of 2 GHz is designed to readout of the weak signal from the C30703FH APD. The TDC is realized by a Spartan-6 field-programmable-gate-array (FPGA) with multiphase method in a resolution of 1ns. The arrival time of all scattering events between two start triggers can be recorded by the TDC. The detector has been used for nuclear resonant scattering study at both Advanced Photon Source and also at Beijing Synchrotron Radiation Facility. For the X-ray energy of 14.4 keV, the time resolution, the full width of half maximum (FWHM) of the detector (APD sensor + fast amplifier) is 0.86 ns, and the whole detector system (APD sensors + fast amplifiers + TDC readout electronics) achieves a time resolution of 1.4 ns.
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Sub-electron read noise and millisecond full-frame readout with the near infrared eAPD array SAPHIRA
NASA Astrophysics Data System (ADS)
Finger, Gert; Baker, Ian; Alvarez, Domingo; Dupuy, Christophe; Ives, Derek; Meyer, Manfred; Mehrgan, Leander; Stegmeier, Jörg; Weller, Harald J.
2016-07-01
In 2007 ESO started a program at SELEX (now LEONARDO) to develop noiseless near infrared HgCdTe electron avalanche photodiode arrays (eAPD)[1][2][3]. This eAPD technology is only way to overcome the limiting CMOS noise barrier of near infrared sensors used for wavefront sensing and fringe tracking. After several development cycles of solid state engineering techniques which can be easily applied to the chosen growth technology of metal organic vapour phase epitaxy (MOVPE), the eAPD arrays have matured and resulted in the SAPHIRA arrays. They have a format of 320x256 pixels with a pitch of 24 μm. They now offer an unmatched combination of sub-electron read noise at millisecond frame readout rates. The first generation of SAPHIRA arrays were only sensitive in H and K-band. With the removal of a wide bandgap buffer layer the arrays are now sensitive from λ=0.8 μm to 2.5 μm with high quantum efficiency over the entire wavelength range. The high temperature anneal applied during the growth process produces material with superb cosmetic quality at an APD gain of over 600. The design of the SAPHIRA ROIC has also been revised and the new ME1000 ROIC has an optimized analogue chain and more flexible readout modes. The clock for the vertical shift register is now under external control. The advantage of this is that correlated-double-sampling and uncorrelated readout in the rolling shutter mode now have a duty cycle of 100% at the maximum frame rate. Furthermore, to reduce the readout noise rows can be read several times before and after row reset. Since the APD gain is sufficiently high that one photon produces many more electrons than the square root of kTC which is the charge uncertainty after reset, signals of one photon per exposure can be easily detected without the need for double correlated sampling. First results obtained with the fringe tracker in GRAVITY and the four SAPHIRA wavefront sensors installed in the CIAO adaptive optics systems of the four 8 meter telescopes of the VLTI have proven the unrivaled performance of the SAPHIRA eAPD technology. A future program is being assembled to develop eAPD arrays having a larger format of 1Kx1K capable of frame rates of 1.2 KHz. There are also good prospects to offer low dark current eAPD technology for large format science focal planes as well.
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2013-01-01
Introduction Hypercapnic acidosis (HCA) that accompanies lung-protective ventilation may be considered permissive (a tolerable side effect), or it may be therapeutic by itself. Cardiovascular effects may contribute to, or limit, the potential therapeutic impact of HCA; therefore, a complex physiological study was performed in healthy pigs to evaluate the systemic and organ-specific circulatory effects of HCA, and to compare them with those of metabolic (eucapnic) acidosis (MAC). Methods In anesthetized, mechanically ventilated and instrumented pigs, HCA was induced by increasing the inspired fraction of CO2 (n = 8) and MAC (n = 8) by the infusion of HCl, to reach an arterial plasma pH of 7.1. In the control group (n = 8), the normal plasma pH was maintained throughout the experiment. Hemodynamic parameters, including regional organ hemodynamics, blood gases, and electrocardiograms, were measured in vivo. Subsequently, isometric contractions and membrane potentials were recorded in vitro in the right ventricular trabeculae. Results HCA affected both the pulmonary (increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR)) and systemic (increase in mean arterial pressure (MAP), decrease in systemic vascular resistance (SVR)) circulations. Although the renal perfusion remained unaffected by any type of acidosis, HCA increased carotid, portal, and, hence, total liver blood flow. MAC influenced the pulmonary circulation only (increase in MPAP and PVR). Both MAC and HCA reduced the stroke volume, which was compensated for by an increase in heart rate to maintain (MAC), or even increase (HCA), the cardiac output. The right ventricular stroke work per minute was increased by both MAC and HCA; however, the left ventricular stroke work was increased by HCA only. In vitro, the trabeculae from the control pigs and pigs with acidosis showed similar contraction force and action-potential duration (APD). Perfusion with an acidic solution decreased the contraction force, whereas APD was not influenced. Conclusions MAC preferentially affects the pulmonary circulation, whereas HCA affects the pulmonary, systemic, and regional circulations. The cardiac contractile function was reduced, but the cardiac output was maintained (MAC), or even increased (HCA). The increased ventricular stroke work per minute revealed an increased work demand placed by acidosis on the heart. PMID:24377654
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GHz low noise short wavelength infrared (SWIR) photoreceivers
NASA Astrophysics Data System (ADS)
Bai, Xiaogang; Yuan, Ping; McDonald, Paul; Boisvert, Joseph; Chang, James; Woo, Robyn; Labios, Eduardo; Sudharsanan, Rengarajan; Krainak, Michael; Yang, Guangning; Sun, Xiaoli; Lu, Wei; McIntosh, Dion; Zhou, Qiugui; Campbell, Joe
2011-06-01
Next generation LIDAR mapping systems require multiple channels of sensitive photoreceivers that operate in the wavelength region of 1.06 to 1.55 microns, with GHz bandwidth and sensitivity less than 300 fW/√Hz. Spectrolab has been developing high sensitivity photoreceivers using InAlAs impact ionization engineering (I2E) avalanche photodiodes (APDs) structures for this application. APD structures were grown using metal organic vapor epitaxy (MOVPE) and mesa devices were fabricated using these structures. We have achieved low excess noise at high gain in these APD devices; an impact ionization parameter, k, of about 0.15 has been achieved at gains >20 using InAlAs/InGaAlAs as a multiplier layer. Electrical characterization data of these devices show dark current less than 2 nA at a gain of 20 at room temperature; and capacitance of 0.4 pF for a typical 75 micron diameter APD. Photoreceivers were built by integrating I2E APDs with a low noise GHz transimpedance amplifier (TIA). The photoreceivers showed a bandwidth of 1 GHz and a noise equivalent power (NEP) of 150 fW/rt(Hz) at room temperature.
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NASA Astrophysics Data System (ADS)
Miyata, Tsuyoshi; Iwata, Tetsuo; Araki, Tsutomu
2006-01-01
We propose a reflection-type pulse oximeter, which employs two pairs of a light-emitting diode (LED) and a gated avalanche photodiode (APD). One LED is a red one with an emission wavelength λ = 635 nm and the other is a near-infrared one with that λ = 945 nm, which are both driven with a pulse mode at a frequency f (=10 kHz). Superposition of a transistor-transistor-logic (TTL) gate pulse on a direct-current (dc) bias, which is set so as not exceeding the breakdown voltage of each APD, makes the APD work in a gain-enhanced operation mode. Each APD is gated at a frequency 2f (=20 kHz) and its output signal is fed into a laboratory-made lock-in amplifier that works in synchronous with the pulse modulation signal of each LED at a frequency f (=10 kHz). A combination of the gated APD and the lock-in like signal detection scheme is useful for the reflection-type pulse oximeter thanks to the capability of detecting a weak signal against a large background (BG) light.
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APDS: the autonomous pathogen detection system.
Hindson, Benjamin J; Makarewicz, Anthony J; Setlur, Ujwal S; Henderer, Bruce D; McBride, Mary T; Dzenitis, John M
2005-04-15
We have developed and tested a fully autonomous pathogen detection system (APDS) capable of continuously monitoring the environment for airborne biological threat agents. The system was developed to provide early warning to civilians in the event of a bioterrorism incident and can be used at high profile events for short-term, intensive monitoring or in major public buildings or transportation nodes for long-term monitoring. The APDS is completely automated, offering continuous aerosol sampling, in-line sample preparation fluidics, multiplexed detection and identification immunoassays, and nucleic acid-based polymerase chain reaction (PCR) amplification and detection. Highly multiplexed antibody-based and duplex nucleic acid-based assays are combined to reduce false positives to a very low level, lower reagent costs, and significantly expand the detection capabilities of this biosensor. This article provides an overview of the current design and operation of the APDS. Certain sub-components of the ADPS are described in detail, including the aerosol collector, the automated sample preparation module that performs multiplexed immunoassays with confirmatory PCR, and the data monitoring and communications system. Data obtained from an APDS that operated continuously for 7 days in a major U.S. transportation hub is reported.
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The performance of Geiger mode avalanche photo-diodes in free space laser communication links
NASA Astrophysics Data System (ADS)
Farrell, Thomas C.
2018-05-01
Geiger mode avalanche photo-diode (APD) arrays, when used as detectors in laser communication (lasercom) receivers, promise better performance at lower signal levels than APDs operated in the linear mode. In this paper, we describe the basic operation of the Geiger mode APD array as a lasercom detector, concentrating on aspects relevant to the link design engineer (rather than, for example, describing the details of the physics of the basic device operation itself). Equations are developed that describe the effects of defocus and hold-off time on the relation between the number of photons detected by the array and the output of photo-electron counts. We show how to incorporate these equations into a link budget. The resulting predictions are validated by comparison against simulation results. Finally, we compare the performance of linear mode APD based receivers and Geiger mode APD array based receivers. Results show the Geiger mode receivers yield better performance, in terms of probability of bit error, at lower signal levels, except on links where there is an exceptionally large amount of background noise. Under those conditions, not surprisingly, the hold-off time degrades performance.
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Effect of Intermolecular Distance on Surface-Plasmon-Assisted Catalysis.
Wu, Shiwei; Liu, Yu; Ma, Caiqing; Wang, Jing; Zhang, Yao; Song, Peng; Xia, Lixin
2018-06-26
4-Aminothiophenol (PATP) and 4-aminophenyl disulfide (APDS) in contact with silver will form H 2 N-C 6 H 4 -S-Ag (PATP-Ag), and under the conditions of surface-enhanced Raman spectroscopy (SERS), a coupling reaction will generate 4,4-dimercaptoazobenzene (DMAB). DMAB is strongly Raman-active, showing strong peaks at ν ≈ 1140, 1390, and 1432 cm -1 , and is widely used in surface-plasmon-assisted catalysis. Using APDS, PATP, p-nitrothiophenol (PNTP), and p-nitrodiphenyl disulfide (NPDS) as probe molecules, Raman spectroscopy and imaging techniques have been used to study the effect of intermolecular distance on surface-plasmon-assisted catalysis. Theoretically, PATP-Ag formed from APDS will be bound at proximal Ag atoms on the Ag surface due to S-S bond cleavage. The results show that APDS is more prone to surface-plasmon-assisted catalytic coupling due to the smaller distance between surface PATP-Ag moieties than those derived from PATP. Therefore, APDS has a higher reaction efficiency, better Raman activity, and better Raman imaging than does PATP. Analogous experiments with PNTP and NPDS gave similar results. Thus, this technique has great application prospects in the fields of surface chemistry and materials chemistry.
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Rivaroxaban modulates electrical and mechanical characteristics of left atrium
2013-01-01
Background Rivaroxaban reduces stroke in patients with atrial fibrillation (AF). Left atrium (LA) plays a critical role in the pathophysiology of AF. However, the electromechanical effects of rivaroxaban on LA are not clear. Results Conventional microelectrodes and a whole-cell patch-clamp were used to record the action potentials (APs) and ionic currents in rabbit LA preparations and isolated single LA cardiomyocytes before and after the administration of rivaroxaban. Rivaroxaban (10, 30, 100, and 300 nM) concentration-dependently reduced LA (n = 7) AP durations at 90% repolarization (APD90) from 76 ± 2 to 79 ± 3, 67 ± 4 (P < 0.05, vs. control), 59 ± 5, (P < 0.01, vs. control), and 56 ± 4 ms (P < 0.005, vs. control), respectively. Rivaroxaban (10, 30, 100, and 300 nM) concentration-dependently increased the LA (n = 7) diastolic tension by 351 ± 69 (P < 0.05, vs. control), 563 ± 136 (P < 0.05, vs. control), 582 ± 119 (P < 0.05, vs. control), and 603 ± 108 mg (P < 0.005, vs. control), respectively, but did not change LA contractility. In the presence of L-NAME (100 μM) and indomethacin (10 μM), additional rivaroxaban (300 nM) treatment did not significantly further increase the LA (n = 7) diastolic tension, but shortened the APD90 from 73 ± 2 to 60 ± 6 ms (P < 0.05, vs. control). Rivaroxaban (100 nM) increased the L-type calcium current and ultra-rapid delayed rectifier potassium current, but did not change the transient outward potassium current in isolated LA cardiomyocytes. Conclusions Rivaroxaban modulates LA electrical and mechanical characteristics with direct ionic current effects. PMID:23497194
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Gomez-Hurtado, Nieves; Boczek, Nicole J.; Kryshtal, Dmytro O.; Johnson, Christopher N.; Sun, Jennifer; Nitu, Florentin R.; Cornea, Razvan L.; Chazin, Walter J.; Calvert, Melissa L.; Tester, David J.; Ackerman, Michael J.; Knollmann, Bjorn C.
2016-01-01
Background Calmodulin (CaM) mutations are associated with severe forms of long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently reported that CaM mutations were found in 13% of genotype-negative LQTS patients, but the prevalence of CaM mutations in genotype-negative CPVT patients is unknown. Here, we identify and characterize CaM mutations in 12 patients with genotype-negative but clinically-diagnosed CPVT. Methods and Results Mutational analysis of CALM1, CALM2 and CALM3 coding regions, in vitro measurement of CaM-Ca2+ (Ca) binding affinity, RyR2-CaM binding, Ca handling, L-type Ca current (LTCC) and action potential duration (APD). We identified a novel CaM mutation – A103V – in CALM3 in 1 of 12 patients (8%), a female who experienced episodes of exertion-induced syncope since age 10, had normal QT interval, and displayed ventricular ectopy during stress testing consistent with CPVT. A103V modestly lowered CaM Ca-binding affinity (3-fold reduction vs WT-CaM), but did not alter CaM binding to RyR2. In permeabilized cardiomyocytes, A103V-CaM (100 nM) promoted spontaneous Ca wave and spark activity, a cellular phenotype of RyR2 activation. Even a 1:3 mixture of A103V-CaM:WT-CaM activated Ca waves, demonstrating functional dominance. Compared to LQTS D96V-CaM, A103V-CaM had significantly less effects on LTCC inactivation and APD, and caused delayed after depolarizations (DADs) and triggered beats in intact cardiomyocytes. Conclusions We discovered a novel CPVT mutation in the CALM3 gene that shares functional characteristics with established CPVT-associated mutations in CALM1. A small proportion of A103V-CaM is sufficient to evoke arrhythmogenic Ca disturbances via RyR2 dysregulation, which explains the autosomal dominant inheritance. PMID:27516456
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Liu, Yang; Wu, Di; Qu, Mei-Yu; He, Jian-Li; Yuan, Mei; Zhao, Miao; Wang, Jian-Xin; He, Jian; Wang, Lu-Qi; Guo, Xin-Jing; Zuo, Meng; Zhao, Shu-Yang; Ma, Mei-Na; Li, Jun-Nan; Shou, Weinian; Qiao, Guo-Fen; Li, Bai-Yan
2016-10-04
Molecular and cellular mechanisms of neuropeptide-Y (NPY)-mediated gender-difference in blood pressure (BP) regulation are largely unknown. Baroreceptor sensitivity (BRS) was evaluated by measuring the response of BP to phenylephrine/nitroprusside. Serum NPY concentration was determined using ELISA. The mRNA and protein expression of NPY receptors were assessed in tissue and single-cell by RT-PCR, immunoblot, and immunohistochemistry. NPY was injected into the nodose while arterial pressure was monitored. Electrophysiological recordings were performed on nodose neurons from rats by patch-clamp technique. The BRS was higher in female than male and ovariectomized rats, while serum NPY concentration was similar among groups. The sex-difference was detected in Y1R, not Y2R protein expression, however, both were upregulated upon ovariectomy and canceled by estrogen replacement. Immunostaining confirmed Y1R and Y2R expression in myelinated and unmyelinated afferents. Single-cell PCR demonstrated that Y1R expression/distribution was identical between A- and C-types, whereas, expressed level of Y2R was ~15 and ~7 folds higher in Ah- and C-types than A-types despite similar distribution. Activation of Y1R in nodose elevated BP, while activation of Y2R did the opposite. Activation of Y1R did not alter action potential duration (APD) of A-types, but activation of Y2R- and Y1R/Y2R in Ah- and C-types frequency-dependently prolonged APD. N-type ICa was reduced in A-, Ah- and C-types when either Y1R, Y2R, or both were activated. The sex-difference in Y1R expression was also observed in NTS. Sex- and afferent-specific expression of Neuropeptide-Y receptors in baroreflex afferent pathway may contribute to sexual-dimorphic neurocontrol of BP regulation.
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Liang, Ping; Lan, Feng; Lee, Andrew S.; Gong, Tingyu; Sanchez-Freire, Veronica; Wang, Yongming; Diecke, Sebastian; Sallam, Karim; Knowles, Joshua W.; Wang, Paul J.; Nguyen, Patricia K.; Bers, Donald M.; Robbins, Robert C.; Wu, Joseph C.
2013-01-01
Background Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with pre-existing heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds. Methods and Results Action potential duration (APD) and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome (LQT), familial hypertrophic cardiomyopathy (HCM), and familial dilated cardiomyopathy (DCM). Disease phenotypes were verified in LQT, HCM, and DCM iPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene (hERG) expressing human embryonic kidney (HEK293) cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in HEK293 cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by APD and quantification of drug-induced arrhythmias such as early after depolarizations (EADs) and delayed after depolarizations (DADs). Conclusions We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, LQT, HCM, and DCM patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than standard hERG test or healthy control hiPSC-CM/hESC-CM screening assays. PMID:23519760
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The Autonomous Pathogen Detection System (APDS)
DOE Office of Scientific and Technical Information (OSTI.GOV)
Morris, J; Dzenitis, J
2004-09-22
Shaped like a mailbox on wheels, it's been called a bioterrorism ''smoke detector.'' It can be found in transportation hubs such as airports and subways, and it may be coming to a location near you. Formally known as the Autonomous Pathogen Detection System, or APDS, this latest tool in the war on bioterrorism was developed at Lawrence Livermore National Laboratory to continuously sniff the air for airborne pathogens and toxins such as anthrax or plague. The APDS is the modern day equivalent of the canaries miners took underground with them to test for deadly carbon dioxide gas. But this canarymore » can test for numerous bacteria, viruses, and toxins simultaneously, report results every hour, and confirm positive samples and guard against false positive results by using two different tests. The fully automated system collects and prepares air samples around the clock, does the analysis, and interprets the results. It requires no servicing or human intervention for an entire week. Unlike its feathered counterpart, when an APDS unit encounters something deadly in the air, that's when it begins singing, quietly. The APDS unit transmits a silent alert and sends detailed data to public health authorities, who can order evacuation and begin treatment of anyone exposed to toxic or biological agents. It is the latest in a series of biodefense detectors developed at DOE/NNSA national laboratories. The manual predecessor to APDS, called BASIS (for Biological Aerosol Sentry and Information System), was developed jointly by Los Alamos and Lawrence Livermore national laboratories. That system was modified to become BioWatch, the Department of Homeland Security's biological urban monitoring program. A related laboratory instrument, the Handheld Advanced Nucleic Acid Analyzer (HANAA), was first tested successfully at LLNL in September 1997. Successful partnering with private industry has been a key factor in the rapid advancement and deployment of biodefense instruments such as these. The APDS technology has been licensed and is currently undergoing commercialization.« less
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Avalanche photodiode based time-of-flight mass spectrometry
DOE Office of Scientific and Technical Information (OSTI.GOV)
Ogasawara, Keiichi, E-mail: kogasawara@swri.edu; Livi, Stefano A.; Desai, Mihir I.
2015-08-15
This study reports on the performance of Avalanche Photodiodes (APDs) as a timing detector for ion Time-of-Flight (TOF) mass spectroscopy. We found that the fast signal carrier speed in a reach-through type APD enables an extremely short timescale response with a mass or energy independent <2 ns rise time for <200 keV ions (1−40 AMU) under proper bias voltage operations. When combined with a microchannel plate to detect start electron signals from an ultra-thin carbon foil, the APD comprises a novel TOF system that successfully operates with a <0.8 ns intrinsic timing resolution even using commercial off-the-shelf constant-fraction discriminators. Bymore » replacing conventional total-energy detectors in the TOF-Energy system, APDs offer significant power and mass savings or an anti-coincidence background rejection capability in future space instrumentation.« less
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Advances in HgCdTe APDs and LADAR Receivers
NASA Technical Reports Server (NTRS)
Bailey, Steven; McKeag, William; Wang, Jinxue; Jack, Michael; Amzajerdian, Farzin
2010-01-01
Raytheon is developing NIR sensor chip assemblies (SCAs) for scanning and staring 3D LADAR systems. High sensitivity is obtained by integrating high performance detectors with gain i.e. APDs with very low noise Readout Integrated Circuits. Unique aspects of these designs include: independent acquisition (non-gated) of pulse returns, multiple pulse returns with both time and intensity reported to enable full 3D reconstruction of the image. Recent breakthrough in device design has resulted in HgCdTe APDs operating at 300K with essentially no excess noise to gains in excess of 100, low NEP <1nW and GHz bandwidths and have demonstrated linear mode photon counting. SCAs utilizing these high performance APDs have been integrated and demonstrated excellent spatial and range resolution enabling detailed 3D imagery both at short range and long ranges. In this presentation we will review progress in high resolution scanning, staring and ultra-high sensitivity photon counting LADAR sensors.
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HgCdTe Avalanche Photodiode Detectors for Airborne and Spaceborne Lidar at Infrared Wavelengths
NASA Technical Reports Server (NTRS)
Sun, Xiaoli; Abshire, James B.; Beck, Jeffrey D.; Mitra, Pradip; Reiff, Kirk; Yang, Guangning
2017-01-01
We report results from characterizing the HgCdTe avalanche photodiode (APD) sensorchip assemblies (SCA) developed for lidar at infrared wavelength using the high density vertically integrated photodiodes (HDVIP) technique. These devices demonstrated high quantum efficiency, typically greater than 90 between 0.8 micrometers and the cut-off wavelength, greater than 600 APD gain, near unity excess noise factor, 6-10 MHz electrical bandwidth and less than 0.5 fW/Hz(exp.1/2) noise equivalent power (NEP). The detectors provide linear analog output with a dynamic range of 2-3 orders of magnitude at a fixed APD gain without averaging, and over 5 orders of magnitude by adjusting the APD and preamplifier gain settings. They have been successfully used in airborne CO2 and CH4 integrated path differential absorption (IPDA) lidar as a precursor for space lidar applications.
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InAlAs/InGaAs avalanche photodiode arrays for free space optical communication.
Ferraro, Mike S; Clark, William R; Rabinovich, William S; Mahon, Rita; Murphy, James L; Goetz, Peter G; Thomas, Linda M; Burris, Harris R; Moore, Christopher I; Waters, William D; Vaccaro, Kenneth; Krejca, Brian D
2015-11-01
In free space optical communication, photodetectors serve not only as communications receivers but also as position sensitive detectors (PSDs) for pointing, tracking, and stabilization. Typically, two separate detectors are utilized to perform these tasks, but recent advances in the fabrication and development of large-area, low-noise avalanche photodiode (APD) arrays have enabled these devices to be used both as PSDs and as communications receivers. This combined functionality allows for more flexibility and simplicity in optical system design without sacrificing the sensitivity and bandwidth performance of smaller, single-element data receivers. This work presents the development of APD arrays rated for bandwidths beyond 1 GHz with measured carrier ionization ratios of approximately 0.2 at moderate APD gains. We discuss the fabrication and characterization of three types of APD arrays along with their performance as high-speed photodetectors.
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Gender differences in contributions of emotion to psychopathy and antisocial personality disorder.
Rogstad, Jill E; Rogers, Richard
2008-12-01
Traditional conceptualizations of psychopathy highlight the importance of affective features as they relate to social deviance; however, little empirical research has actually investigated specific roles of emotion and emotion processing with respect to antisocial conduct. Antisocial personality disorder (APD), prevalent in forensic populations, is commonly associated with psychopathy despite the notable omission of such core affective features in its diagnosis. In this paper, we review the empirical literature on the contribution of emotion to psychopathy and APD, highlighting in particular research on emotion processing and various facets of emotional expression, including empathy and alexithymia. Research findings are discussed on gender differences in emotional functioning and their likely effects on the assessment of psychopathy and APD. Given the known gender differences in the expressions of emotion, the article concludes with recommendations to bridge research for different offender groups, including psychopathy and APD.
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NASA Technical Reports Server (NTRS)
Steib, Michael
1991-01-01
The APD software features include: On-line help, Three level architecture, (Logic environments, Setup/Application environment, Data environment), Explanation capability, and File handling. The kinds of experimentation and record keeping that leads to effective expert systems is facilitated by: (1) a library of inferencing modules (in the logic environment); (2) an explanation capability which reveals logic strategies to users; (3) automated file naming conventions; (4) an information retrieval system; and (5) on-line help. These aid with effective use of knowledge, debugging and experimentation. Since the APD software anticipates the logical rules becoming complicated, it is embedded in a production system language (CLIPS) to insure the full power of the production system paradigm of CLIPS and availability of the procedural language C. The development is discussed of the APD software and three example applications: toy, experimental, and operational prototype for submarine maintenance predictions.
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Cognitive Control Deficits Associated with Antisocial Personality Disorder and Psychopathy
Zeier, Joshua D.; Baskin-Sommers, Arielle R.; Newman, Joseph P.; Racer, Kristina Hiatt
2011-01-01
Antisociality has been linked to a variety of executive functioning deficits, including poor cognitive control. Surprisingly, cognitive control deficits are rarely found in psychopathic individuals, despite their notoriously severe and persistent antisocial behavior. In fact, primary (low-anxious) psychopathic individuals display superior performance on cognitive control-type tasks under certain circumstances. To clarify these seemingly contradictory findings, we administered a response competition (i.e. flanker) task to incarcerated offenders, who were assessed for Antisocial Personality Disorder (APD) symptoms and psychopathy. As hypothesized, APD related to poorer accuracy, especially on incongruent trials. Contrary to expectation, however, the same pattern of results was found in psychopathy. Additional analyses indicated that these effects of APD and psychopathy were associated with overlapping variance. The findings suggest that psychopathy and APD symptoms are both associated with deficits in cognitive control, and that this deficit relates to general antisociality as opposed to a specific antisocial syndrome. PMID:22452754
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Shepherd, Stephane M; Campbell, Rachel E; Ogloff, James R P
2018-02-01
This study identified the presence of psychopathy (as measured by the PCL-R/PCL:SV instruments) and antisocial personality disorder (APD) and their relationship with future reconviction in an Australian forensic sample ( N = 136) of patients with a mental disorder. Patients were tracked for over 4 years postrelease to determine associations between a diagnosis of APD/psychopathy and reoffense. Patients with higher psychopathy scores were found to have an increased likelihood of reincarceration, a higher rate of reconviction, and were reconvicted earlier compared with patients with lower psychopathy scores. Patients with APD were more likely to be reconvicted and reincarcerated during the follow-up period than patients without an APD diagnosis. Despite demonstrating associations with general reconviction, the PCL instruments did not exhibit statistically significant relationships with violence. Implications for the clinical identification of personality disordered patients in forensic settings are discussed.
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Detecting Bioaerosols When Time Is of the Essence
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hazi, A
About seven years ago, Livermore researchers received seed funding from the Laboratory Directed Research and Development Program to develop an instrument that counters bioterrorism by providing a rapid early warning system for pathogens, such as anthrax. (See S&TR, January/February 2002, pp. 24-26.) That instrument, the Autonomous Pathogen Detection System (APDS), is now ready for deployment to better protect the public from a bioaerosol attack, and the development team has been honored with a 2004 R&D 100 Award. The lectern-size APDS can be placed in airports, office buildings, performing arts centers, mass transit systems, sporting arenas--anywhere an attack might be launched.more » APDS was designed to get results fast and get them right, without false positives. Biological scientist Richard Langlois, who spearheaded the APDS development effort, explains, ''The system provides results on the spot. Faster results allow a faster emergency response, which in the end means saving lives.''« less
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An infrared optical pacing system for screening cardiac electrophysiology in human cardiomyocytes.
McPheeters, Matthew T; Wang, Yves T; Werdich, Andreas A; Jenkins, Michael W; Laurita, Kenneth R
2017-01-01
Human cardiac myocytes derived from pluripotent stem cells (hCM) have invigorated interest in genetic disease mechanisms and cardiac safety testing; however, the technology to fully assess electrophysiological function in an assay that is amenable to high throughput screening has lagged. We describe a fully contactless system using optical pacing with an infrared (IR) laser and multi-site high fidelity fluorescence imaging to assess multiple electrophysiological parameters from hCM monolayers in a standard 96-well plate. Simultaneous multi-site action potentials (FluoVolt) or Ca2+ transients (Fluo4-AM) were measured, from which high resolution maps of conduction velocity and action potential duration (APD) were obtained in a single well. Energy thresholds for optical pacing were determined for cell plating density, laser spot size, pulse width, and wavelength and found to be within ranges reported previously for reliable pacing. Action potentials measured using FluoVolt and a microelectrode exhibited the same morphology and rate of depolarization. Importantly, we show that this can be achieved accurately with minimal damage to hCM due to optical pacing or fluorescence excitation. Finally, using this assay we demonstrate that hCM exhibit reproducible changes in repolarization and impulse conduction velocity for Flecainide and Quinidine, two well described reference compounds. In conclusion, we demonstrate a high fidelity electrophysiological screening assay that incorporates optical pacing with IR light to control beating rate of hCM monolayers.
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Using delay differential equations to induce alternans in a model of cardiac electrophysiology.
Eastman, Justin; Sass, Julian; Gomes, Johnny M; Dos Santos, Rodrigo Weber; Cherry, Elizabeth M
2016-09-07
Cardiac electrical alternans is a period-2 dynamical behavior with alternating long and short action potential durations (APD) that often precedes dangerous arrhythmias associated with cardiac arrest. Despite the importance of alternans, many current ordinary differential equations models of cardiac electrophysiology do not produce alternans, thereby limiting the use of these models for studying the mechanisms that underlie this condition. Because delay differential equations (DDEs) commonly induce complex dynamics in other biological systems, we investigate whether incorporating DDEs can lead to alternans development in cardiac models by studying the Fox et al. canine ventricular action potential model. After suppressing the alternans in the original model, we show that alternans can be obtained by introducing DDEs in the model gating variables, and we quantitatively compare the DDE-induced alternans with the alternans present in the original model. We analyze the behavior of the voltage, currents, and gating variables of the model to study the effects of the delays and to determine how alternans develops in that setting, and we discuss the mathematical and physiological implications of our findings. In future work, we aim to apply our approach to induce alternans in models that do not naturally exhibit such dynamics. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Analytically based photon scatter modeling for a multipinhole cardiac SPECT camera.
Pourmoghaddas, Amir; Wells, R Glenn
2016-11-01
Dedicated cardiac SPECT scanners have improved performance over standard gamma cameras allowing reductions in acquisition times and/or injected activity. One approach to improving performance has been to use pinhole collimators, but this can cause position-dependent variations in attenuation, sensitivity, and spatial resolution. CT attenuation correction (AC) and an accurate system model can compensate for many of these effects; however, scatter correction (SC) remains an outstanding issue. In addition, in cameras using cadmium-zinc-telluride-based detectors, a large portion of unscattered photons is detected with reduced energy (low-energy tail). Consequently, application of energy-based SC approaches in these cameras leads to a higher increase in noise than with standard cameras due to the subtraction of true counts detected in the low-energy tail. Model-based approaches with parallel-hole collimator systems accurately calculate scatter based on the physics of photon interactions in the patient and camera and generate lower-noise estimates of scatter than energy-based SC. In this study, the accuracy of a model-based SC method was assessed using physical phantom studies on the GE-Discovery NM530c and its performance was compared to a dual energy window (DEW)-SC method. The analytical photon distribution (APD) method was used to calculate the distribution of probabilities that emitted photons will scatter in the surrounding scattering medium and be subsequently detected. APD scatter calculations for 99m Tc-SPECT (140 ± 14 keV) were validated with point-source measurements and 15 anthropomorphic cardiac-torso phantom experiments and varying levels of extra-cardiac activity causing scatter inside the heart. The activity inserted into the myocardial compartment of the phantom was first measured using a dose calibrator. CT images were acquired on an Infinia Hawkeye (GE Healthcare) SPECT/CT and coregistered with emission data for AC. For comparison, DEW scatter projections (120 ± 6 keV ) were also extracted from the acquired list-mode SPECT data. Either APD or DEW scatter projections were subtracted from corresponding 140 keV measured projections and then reconstructed with AC (APD-SC and DEW-SC). Quantitative accuracy of the activity measured in the heart for the APD-SC and DEW-SC images was assessed against dose calibrator measurements. The difference between modeled and acquired projections was measured as the root-mean-squared-error (RMSE). APD-modeled projections for a clinical cardiac study were also evaluated. APD-modeled projections showed good agreement with SPECT measurements and had reduced noise compared to DEW scatter estimates. APD-SC reduced mean error in activity measurement compared to DEW-SC in images and the reduction was statistically significant where the scatter fraction (SF) was large (mean SF = 28.5%, T-test p = 0.007). APD-SC reduced measurement uncertainties as well; however, the difference was not found to be statistically significant (F-test p > 0.5). RMSE comparisons showed that elevated levels of scatter did not significantly contribute to a change in RMSE (p > 0.2). Model-based APD scatter estimation is feasible for dedicated cardiac SPECT scanners with pinhole collimators. APD-SC images performed better than DEW-SC images and improved the accuracy of activity measurement in high-scatter scenarios.
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NASA Astrophysics Data System (ADS)
Foubert, K.; Lasfargues, G.; Mathieu, L.; Benahmed, S.; Vojetta, G.; Rothman, J.; Benoît à la Guillaume, Q.; Calvo, Vincent; Picot-Clemente, Jérémy; Le Mounier, Florent; Gibert, Fabien
2013-03-01
The remarkable properties (internal gain larger than 100 and close to unity excess noise factor) of Short Wave Infrared (SWIR) HgCdTe electron-initiated Avalanche Photodiodes (e-APDs) are put to good use to demanding applications, i.e. spectroscopy and LIDAR. Knowing the requirements of both situations, we have designed specific models based on highly sensitive single elements APDs and adapted proximity electronics. On one hand, we use the e-APDs low noise equivalent power (NEP) at 180K (few fW/Hz1/2). We simultaneously designed a specific Transimpedance Amplifier (TIA) which allows us to take advantage of the low APD NEP. The combination of both elements along with a dedicated cryostat enables direct LIDAR detection at moderate bandwidth (BW = 20 MHz) without the need for long time averaging, which is crucial in far field (>= 5 km) analysis. One the other hand, we have optimized a low-noise and low-frequency LN2 cooled prototype operating with an external commercial amplifier. It allows us to observe the photoluminescence of Ge nanostructures in the range 1.5-2.5 μm with a significantly increased SNR along with a reduce pump laser power. The possibility to use these detectors in the photon counting limit will be discussed in light of our recent results. In parallel, we present preliminary time response measurements performed on SWIR APD suggesting that a higher GHz BW could be reached with this type of detector. This is however subjected to optical optimization at the moment.
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Gress, Steeve; Lemoine, Sandrine; Puddu, Paolo-Emilio; Séralini, Gilles-Eric; Rouet, René
2015-10-01
Roundup (R), a glyphosate (G)-based herbicide (GBH), containing unknown adjuvants is widely dispersed around the world. Used principally by farmers, intoxications have increasingly been reported. We have studied R effects (containing 36 % of G) on right ventricular tissues (male Sprague-Dawley rats, up to 20,000 ppm and female New Zealand rabbits, at 25 and 50 ppm), to investigate R cardiac electrophysiological actions in vitro. We tested the reduced Ca(++) intracellular uptake mechanism as one potential cause of the electrical abnormalities after GBH superfusion, using the Na(+)/K(+)-ATPase inhibitor ouabain or the 1,4-dihydropyridine L-type calcium channel agonist BAY K 8644 which increases I Ca. R concentrations were selected based on human blood ranges found after acute intoxication. The study showed dose-dependent V max, APD50 and APD90 variations during 45 min of R superfusion. At the highest concentrations tested, there was a high incidence of conduction blocks, and 30-min washout with normal Tyrode solution did not restore excitability. We also observed an increased incidence of arrhythmias at different doses of R. Ouabain and BAY K 8644 prevented V max decrease, APD90 increase and the cardiac inexcitability induced by R 50 ppm. Glyphosate alone (18 and 180 ppm) had no significant electrophysiological effects. Thus, the action potential prolonging effect of R pointing to I Ca interference might explain both conduction blocks and proarrhythmia in vitro. These mechanisms may well be causative of QT prolongation, atrioventricular conduction blocks and arrhythmias in man after GBH acute intoxications as reported in retrospective hospital records.
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Update on Linear Mode Photon Counting with the HgCdTe Linear Mode Avalanche Photodiode
NASA Technical Reports Server (NTRS)
Beck, Jeffrey D.; Kinch, Mike; Sun, Xiaoli
2014-01-01
The behavior of the gain-voltage characteristic of the mid-wavelength infrared cutoff HgCdTe linear mode avalanche photodiode (e-APD) is discussed both experimentally and theoretically as a function of the width of the multiplication region. Data are shown that demonstrate a strong dependence of the gain at a given bias voltage on the width of the n- gain region. Geometrical and fundamental theoretical models are examined to explain this behavior. The geometrical model takes into account the gain-dependent optical fill factor of the cylindrical APD. The theoretical model is based on the ballistic ionization model being developed for the HgCdTe APD. It is concluded that the fundamental theoretical explanation is the dominant effect. A model is developed that combines both the geometrical and fundamental effects. The model also takes into account the effect of the varying multiplication width in the low bias region of the gain-voltage curve. It is concluded that the lower than expected gain seen in the first 2 × 8 HgCdTe linear mode photon counting APD arrays, and higher excess noise factor, was very likely due to the larger than typical multiplication region length in the photon counting APD pixel design. The implications of these effects on device photon counting performance are discussed.
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NASA Technical Reports Server (NTRS)
Clements, E. B.; Carlton, A. K.; Joyce, C. J.; Schwadron, N. A.; Spence, H. E.; Sun, X.; Cahoy, K.
2016-01-01
Space weather is a major concern for radiation-sensitive space systems, particularly for interplanetary missions, which operate outside of the protection of Earth's magnetic field. We examine and quantify the effects of space weather on silicon avalanche photodiodes (SiAPDs), which are used for interplanetary laser altimeters and communications systems and can be sensitive to even low levels of radiation (less than 50 cGy). While ground-based radiation testing has been performed on avalanche photodiode (APDs) for space missions, in-space measurements of SiAPD response to interplanetary space weather have not been previously reported. We compare noise data from the Lunar Reconnaissance Orbiter (LRO) Lunar Orbiter Laser Altimeter (LOLA) SiAPDs with radiation measurements from the onboard Cosmic Ray Telescope for the Effects of Radiation (CRaTER) instrument. We did not find any evidence to support radiation as the cause of changes in detector threshold voltage during radiation storms, both for transient detector noise and long-term average detector noise, suggesting that the approximately 1.3 cm thick shielding (a combination of titanium and beryllium) of the LOLA detectors is sufficient for SiAPDs on interplanetary missions with radiation environments similar to what the LRO experienced (559 cGy of radiation over 4 years).
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NASA Astrophysics Data System (ADS)
Fang, X. C.; Hu-Guo, Ch.; Ollivier-Henry, N.; Brasse, D.; Hu, Y.
2010-06-01
This paper represents the design of a low-noise, wide band multi-channel readout integrated circuit (IC) used as front end readout electronics of avalanche photo diodes (APD) dedicated to a small animal positron emission tomography (PET) system. The first ten-channel prototype chip (APD-Chip) of the analog parts has been designed and fabricated in a 0.35 μm CMOS process. Every channel of the APD_Chip includes a charge-sensitive preamplifier (CSA), a CR-(RC)2 shaper, and an analog buffer. In a channel, the CSA reads charge signals (10 bits dynamic range) from an APD array having 10 pF of capacitance per pixel. A linearized degenerated differential pair which ensures high linearity in all dynamical range is used as the high feedback resistor for preventing pile up of signals. The designed CSA has the capability of compensating automatically up to 200 nA leakage current from the detector. The CR-(RC)2 shaper filters and shapes the output signal of the CSA. An equivalent input noise charge obtained from test is 275 e -+ 10 e-/pF. In this paper the prototype is presented for both its theoretical analysis and its test results.
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Reliable InP-based Geiger-mode avalanche photodiode arrays
NASA Astrophysics Data System (ADS)
Smith, Gary M.; McIntosh, K. Alex; Donnelly, Joseph P.; Funk, Joseph E.; Mahoney, Leonard J.; Verghese, Simon
2009-05-01
Arrays as large as 256 x 64 of single-photon counting avalanche photodiodes have been developed for defense applications in free-space communication and laser radar. Focal plane arrays (FPAs) sensitive to both 1.06 and 1.55 μm wavelength have been fabricated for these applications. At 240 K and 4 V overbias, the dark count rate (DCR) of 15 μm diameter devices is typically 250 Hz for 1.06 μm sensitive APDs and 1 kHz for 1.55 μm APDs. Photon detection efficiencies (PDE) at 4 V overbias are about 45% for both types of APDs. Accounting for microlens losses, the full FPA has a PDE of 30%. The reset time needed for a pixel to avoid afterpulsing at 240 K is about 3-4 μsec. These devices have been used by system groups at Lincoln Laboratory and other defense contractors for building operational systems. For these fielded systems the device reliability is a strong concern. Individual APDs as well as full arrays have been run for over 1000 hrs of accelerated testing to verify their stability. The reliability of these GM-APDs is shown to be under 10 FITs at operating temperatures of 250 K, which also corresponds to an MTTF of 17,100 yrs.
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Characterization of Advanced Avalanche Photodiodes for Water Vapor Lidar Receivers
NASA Technical Reports Server (NTRS)
Refaat, Tamer F.; Halama, Gary E.; DeYoung, Russell J.
2000-01-01
Development of advanced differential absorption lidar (DIAL) receivers is very important to increase the accuracy of atmospheric water vapor measurements. A major component of such receivers is the optical detector. In the near-infrared wavelength range avalanche photodiodes (APD's) are the best choice for higher signal-to-noise ratio, where there are many water vapor absorption lines. In this study, characterization experiments were performed to evaluate a group of silicon-based APD's. The APD's have different structures representative of different manufacturers. The experiments include setups to calibrate these devices, as well as characterization of the effects of voltage bias and temperature on the responsivity, surface scans, noise measurements, and frequency response measurements. For each experiment, the setup, procedure, data analysis, and results are given and discussed. This research was done to choose a suitable APD detector for the development of an advanced atmospheric water vapor differential absorption lidar detection system operating either at 720, 820, or 940 nm. The results point out the benefits of using the super low ionization ratio (SLIK) structure APD for its lower noise-equivalent power, which was found to be on the order of 2 to 4 fW/Hz(sup (1/2)), with an appropriate optical system and electronics. The water vapor detection systems signal-to-noise ratio will increase by a factor of 10.
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Detection of cat-eye effect echo based on unit APD
NASA Astrophysics Data System (ADS)
Wu, Dong-Sheng; Zhang, Peng; Hu, Wen-Gang; Ying, Jia-Ju; Liu, Jie
2016-10-01
The cat-eye effect echo of optical system can be detected based on CCD, but the detection range is limited within several kilometers. In order to achieve long-range even ultra-long-range detection, it ought to select APD as detector because of the high sensitivity of APD. The detection system of cat-eye effect echo based on unit APD is designed in paper. The implementation scheme and key technology of the detection system is presented. The detection performances of the detection system including detection range, detection probability and false alarm probability are modeled. Based on the model, the performances of the detection system are analyzed using typical parameters. The results of numerical calculation show that the echo signal-to-noise ratio is greater than six, the detection probability is greater than 99.9% and the false alarm probability is less tan 0.1% within 20 km detection range. In order to verify the detection effect, we built the experimental platform of detection system according to the design scheme and carry out the field experiments. The experimental results agree well with the results of numerical calculation, which prove that the detection system based on the unit APD is feasible to realize remote detection for cat-eye effect echo.
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Wang, Hongwei; Yao, Yating; Li, Ya; Ma, Shujuan; Peng, Xiaojun; Ou, Junjie; Ye, Mingliang
2017-08-01
An open tubular (OT) column (25 μm i.d.) was prepared by in situ ring-opening polymerization of octaglycidyldimethylsilyl polyhedral oligomeric silsesquioxanes (POSS-epoxy) with 4-aminophenyl disulfide (APDS) in a binary porogenic system of ethanol/H 2 O. It was found that porogenic composition played an important role in the formation of OT stationary phases. The ratio of ethanol/H 2 O at 6/1 (v/v) would lead to the fabrication of hybrid monoliths, while the ratio of ethanol/H 2 O at 13/1 (v/v) would result in the synthesis of OT phases. In addition, the effects of precursor content and reaction duration on the thickness of OT stationary phases were investigated. Either lower precursor content or shorter reaction duration would produce thinner layer of OT column. The repeatability of OT columns was evaluated through relative standard deviation (RSD%) with benzene as the analyte. The run-to-run, column-to-column and batch-to-batch repeatabilities were 1.7%, 4.8% and 5.6%, respectively, exhibiting satisfactory repeatability of the OT column. Then tryptic digest of mouse liver proteins was used to evaluate the performance of the resulting OT columns (25 μm i.d. × 2.5 m in length) by cLC-MS/MS analysis, demonstrating their potential in proteome analysis. Copyright © 2017 Elsevier B.V. All rights reserved.
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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.
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NASA Technical Reports Server (NTRS)
Hunt, W. D.; Brennan, K. F.; Summers, C. J.; Yun, Ilgu
1994-01-01
Reliability modeling and parametric yield prediction of GaAs/AlGaAs multiple quantum well (MQW) avalanche photodiodes (APDs), which are of interest as an ultra-low noise image capture mechanism for high definition systems, have been investigated. First, the effect of various doping methods on the reliability of GaAs/AlGaAs multiple quantum well (MQW) avalanche photodiode (APD) structures fabricated by molecular beam epitaxy is investigated. Reliability is examined by accelerated life tests by monitoring dark current and breakdown voltage. Median device lifetime and the activation energy of the degradation mechanism are computed for undoped, doped-barrier, and doped-well APD structures. Lifetimes for each device structure are examined via a statistically designed experiment. Analysis of variance shows that dark-current is affected primarily by device diameter, temperature and stressing time, and breakdown voltage depends on the diameter, stressing time and APD type. It is concluded that the undoped APD has the highest reliability, followed by the doped well and doped barrier devices, respectively. To determine the source of the degradation mechanism for each device structure, failure analysis using the electron-beam induced current method is performed. This analysis reveals some degree of device degradation caused by ionic impurities in the passivation layer, and energy-dispersive spectrometry subsequently verified the presence of ionic sodium as the primary contaminant. However, since all device structures are similarly passivated, sodium contamination alone does not account for the observed variation between the differently doped APDs. This effect is explained by the dopant migration during stressing, which is verified by free carrier concentration measurements using the capacitance-voltage technique.
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Design and Development of 256x256 Linear Mode Low-Noise Avalanche Photodiode Arrays
NASA Technical Reports Server (NTRS)
Yuan, Ping; Sudharsanan, Rengarajan; Bai, Xiaogang; Boisvert, Joseph; McDonald, Paul; Chang, James
2011-01-01
A larger format photodiode array is always desirable for many LADAR imaging applications. However, as the array format increases, the laser power or the lens aperture has to increase to maintain the same flux per pixel thus increasing the size, weight and power of the imaging system. In order to avoid this negative impact, it is essential to improve the pixel sensitivity. The sensitivity of a short wavelength infrared linear-mode avalanche photodiode (APD) is a delicate balance of quantum efficiency, usable gain, excess noise factor, capacitance, and dark current of APD as well as the input equivalent noise of the amplifier. By using InA1As as a multiplication layer in an InP-based APD, the ionization coefficient ratio, k, is reduced from 0.40 (lnP) to 0.22, and the excess noise is reduced by about 50%. An additional improvement in excess noise of 25% was achieved by employing an impact-ionization-engineering structure with a k value of 0.15. Compared with the traditional InP structure, about 30% reduction in the noise-equivalent power with the following amplifier can be achieved. Spectrolab demonstrated 30-um mesa APD pixels with a dark current less than 10 nA and a capacitance of 60 fF at gain of 10. APD gain uninformity determines the usable gain of most pixels in an array, which is critical to focal plane array sensitivity. By fine tuning the material growth and device process, a break-down-voltage standard deviation of 0.1 V and gain of 30 on individual pixels were demonstrated in our 256x256 linear-mode APD arrays.
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Evaluation of a HgCdTe e-APD based detector for 2 μm CO2 DIAL application.
Dumas, Arnaud; Rothman, Johan; Gibert, Fabien; Édouart, Dimitri; Lasfargues, Gilles; Cénac, Claire; Mounier, Florian Le; Pellegrino, Jessica; Zanatta, Jean-Paul; Bardoux, Alain; Tinto, Francesc; Flamant, Pierre
2017-09-20
Benefiting from close to ideal amplification properties (high gain, low dark current, and low excess noise factor), HgCdTe electron initiated avalanche photodiode (e-APD) technology exhibits state of the art sensitivity, thus being especially relevant for applications relying on low light level detection, such as LIDAR (Light Detection And Ranging). In addition, the tunable gap of the Hg 1-x Cd x Te alloy enables coverage of the short wavelength infrared (SWIR) and especially the 2 μm spectral range. For these two reasons, a HgCdTe e-APD based detector is a promising candidate for future differential absorption LIDAR missions targeting greenhouse gas absorption bands in SWIR. In this study, we report on the design and evaluation of such a HgCdTe e-APD based detector. The first part focuses on detector architecture and performance. Key figures of merit are: 2.8 μm cutoff wavelength, 200 μm diameter almost circular sensitive area, 185 K operating temperature (thermo-electric cooling), 22 APD gain (at 12 V reverse bias), 360 kΩ transimpedance gain, and 60 fWHz -0.5 noise equivalent power (at 12 V reverse bias). The second part presents an analysis of atmospheric LIDAR signals obtained by mounting the HgCdTe e-APD based detector on the 2 μm differential absorption LIDAR developed at the Laboratoire de Météorologie Dynamique and dedicated to CO 2 monitoring. Discussion emphasizes random and systematic errors in LIDAR measurements regarding breadboard detector characterization. In particular, we investigate the influence of parasitic tails in detector impulse response on short range DIAL measurements.
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Coulter, Tanya I; Chandra, Anita; Bacon, Chris M; Babar, Judith; Curtis, James; Screaton, Nick; Goodlad, John R; Farmer, George; Steele, Cathal Laurence; Leahy, Timothy Ronan; Doffinger, Rainer; Baxendale, Helen; Bernatoniene, Jolanta; Edgar, J David M; Longhurst, Hilary J; Ehl, Stephan; Speckmann, Carsten; Grimbacher, Bodo; Sediva, Anna; Milota, Tomas; Faust, Saul N; Williams, Anthony P; Hayman, Grant; Kucuk, Zeynep Yesim; Hague, Rosie; French, Paul; Brooker, Richard; Forsyth, Peter; Herriot, Richard; Cancrini, Caterina; Palma, Paolo; Ariganello, Paola; Conlon, Niall; Feighery, Conleth; Gavin, Patrick J; Jones, Alison; Imai, Kohsuke; Ibrahim, Mohammad A A; Markelj, Gašper; Abinun, Mario; Rieux-Laucat, Frédéric; Latour, Sylvain; Pellier, Isabelle; Fischer, Alain; Touzot, Fabien; Casanova, Jean-Laurent; Durandy, Anne; Burns, Siobhan O; Savic, Sinisa; Kumararatne, D S; Moshous, Despina; Kracker, Sven; Vanhaesebroeck, Bart; Okkenhaug, Klaus; Picard, Capucine; Nejentsev, Sergey; Condliffe, Alison M; Cant, Andrew James
2017-02-01
Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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Characterization of irradiated APDs for picosecond time measurements
NASA Astrophysics Data System (ADS)
Centis Vignali, M.; Dalal, R.; Gallinaro, M.; Harrop, B.; Jain, G.; Lu, C.; McClish, M.; McDonald, K. T.; Moll, M.; Newcomer, F. M.; Ugobono, S. Otero; White, S.
2018-01-01
For their operation at the CERN High Luminosity Large Hadron Collider (HL-LHC), the ATLAS and CMS experiments are planning to implement dedicated systems to measure the time of arrival of minimum ionizing particles with an accuracy of about 30 ps. The timing detectors will be subjected to radiation levels corresponding up to a 1-MeV neutrons fluence (Φeq) of 1015 cm-2 for the goal integrated luminosity of HL-LHC of 3000 fb-1. In this paper, deep-diffused Avalanche Photo Diodes (APDs) produced by Radiation Monitoring Devices are examined as candidate timing detectors for HL-LHC applications. These APDs are operated at 1.8 kV, resulting in a gain of up to 500. The timing performance of the detectors is evaluated using a pulsed laser. The effects of radiation damage on current, signal amplitude, noise, and timing performance of the APDs are evaluated using detectors irradiated with neutrons up to Φeq = 1015 cm-2.
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Ha, Jung-Eun; Jung, Se-Hwan; Jin, Bo-Hyoung; Lee, Byoung-Jin; Bae, Kwang-Hak
2013-09-01
The National Oral Health Screening Program (NOHSP) is a general population-based program in Korea. The objective of this study was to assess the association between participation in the NOHSP and dental visit for periapical abscess (PA) and advanced periodontal disease (APD) among Korean adults. Data were obtained for subjects from the National Health Insurance database. The authors conducted a retrospective cohort study of 9358 randomly selected subjects who were between 40 and 64 years old in 2002. The outcomes of dental visit for PA or APD from the years 2003 to 2007 were compared between the screening and nonscreening groups. The nonscreening group had 19% higher risk of PA and 15% higher risk of APD. This study suggests that the NOHSP may decrease the risk of dental visit because of PA and APD by preventing the progress of lesion to the advanced stage among Korean adults.
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Osisanya, Ayo; Adewunmi, Abiodun T
2018-02-01
The need to develop a measure of managing children with a single profile of auditory processing disorders (APDs), and differentiate between true and artefactual improvements necessitated the study. The study also sought to determine the efficacy of interventions - both single and combined on APD, against no-treatment. A randomised controlled trial of interventions (RCT) was adopted. Participants were randomly allocated to each of the intervention groups or the no intervention group. The 10 weeks intervention included 45 minutes three times a week therapeutic intervention on listening with noise and sound localisation ability in the home and school environments. 80 pupils (7-11 years) with a single profile of APD participated in the study. Treatments were effective on the cocktail party and sound localisation. The best result was realised with the combined therapy (CT), and there was no significant difference in performance in the remaining treatment groups. The intervention groups were beneficial to pupils with APD and should be adopted by clinicians.
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Current 2-μm dial measurements of atmospheric CO2 and expected results from space using new MCT APDS
NASA Astrophysics Data System (ADS)
Dumas, A.; Gibert, F.; Rothman, J.; Édouart, D.; Le Mounier, F.; Cénac, C.
2017-11-01
In the framework of CO2 monitoring in the Atmospheric Boundary Layer (ABL), a ground-based 2-μm Differential Absorption Lidar (DIAL) has been developed at the Laboratoire de Météorologie Dynamique (LMD) in Palaiseau. In order to derive flux information, this system has been set up with coherent detection, which allows to combine CO2 density measurements with wind velocity measurements. On the other hand, new advances in the field of Mercury Cadmium Tellure (MCT) Avalanche Photodiodes (APDs) open the way for high-precision measurements in direct detection ultimately from space. In this study, we first report on state of the art measurements obtained with the current coherent DIAL system before presenting expected results for a similar laser transmitter equipped with MCT APDs. For this latter part, we use a numerical model which relies on APDs performance data provided by the Laboratoire d'Électronique et de Technologie de l'Information (LETI).
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Determination of the excess noise of avalanche photodiodes integrated in 0.35-μm CMOS technologies
NASA Astrophysics Data System (ADS)
Jukić, Tomislav; Brandl, Paul; Zimmermann, Horst
2018-04-01
The excess noise of avalanche photodiodes (APDs) integrated in a high-voltage (HV) CMOS process and in a pin-photodiode CMOS process, both with 0.35-μm structure sizes, is described. A precise excess noise measurement technique is applied using a laser source, a spectrum analyzer, a voltage source, a current meter, a cheap transimpedance amplifier, and a personal computer with a MATLAB program. In addition, usage for on-wafer measurements is demonstrated. The measurement technique is verified with a low excess noise APD as a reference device with known ratio k = 0.01 of the impact ionization coefficients. The k-factor of an APD developed in HV CMOS is determined more accurately than known before. In addition, it is shown that the excess noise of the pin-photodiode CMOS APD depends on the optical power for avalanche gains above 35 and that modulation doping can suppress this power dependence. Modulation doping, however, increases the excess noise.
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Applicability of central auditory processing disorder models.
Jutras, Benoît; Loubert, Monique; Dupuis, Jean-Luc; Marcoux, Caroline; Dumont, Véronique; Baril, Michèle
2007-12-01
Central auditory processing disorder ([C]APD) is a relatively recent construct that has given rise to 2 theoretical models: the Buffalo Model and the Bellis/Ferre Model. These models describe 4 and 5 (C)APD categories, respectively. The present study examines the applicability of these models to clinical practice. Neither of these models was based on data from peer-reviewed sources. This is a retrospective study that reviewed 178 records of children diagnosed with (C)APD, of which 48 were retained for analysis. More than 80% of the children could be classified into one of the Buffalo Model categories, while more than 90% remained unclassified under the Bellis/Ferre Model. This discrepancy can be explained by the fact that the classification of the Buffalo Model is based primarily on a single central auditory test (Staggered Spondaic Word), whereas the Bellis/Ferre Model classification uses a combination of auditory test results. The 2 models provide a conceptual framework for (C)APD, but they must be further refined to be fully applicable in clinical settings.
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Environmental Radiation Measurements on MIR Station
NASA Astrophysics Data System (ADS)
Benton, E. V.; Frank, A. L.; Benton, E. R.
1997-04-01
Environmental radiation levels on the Russian space station Mir are being monitored under differing shielding conditions by a series of six area passive dosimeters (APDs) placed at individual locations inside the Core and Kvant 2 modules, and by an External Dosimeter Array (EDA) to be-deployed on the exterior surface of the Kvant 2 module. Each APD and the EDA contains CR-39 plastic nuclear track detectors (PNTDs) for measurement of LET spectra and TLDs for absorbed dose measurements. Two of the missions, NASA-2/Mir-21 and NASA-3/Mir-22 have been completed and the six APDs from each mission returned to Earth from Mir. This report covers progress to date on the analysis of TLDs and PNTDs from these two missions. For NASA-2/Mir-21, average mission absorbed dose rates varied from 271 to 407 micro-Gy/d at the APDS. For NASA-3/Mir-22, average mission absorbed dose rates varied from 265 to 421 micro-Gy/d.
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The histopathologic features of autoimmune progesterone dermatitis.
James, Travis; Ghaferi, Jessica; LaFond, Ann
2017-01-01
The histologic features of autoimmune progesterone dermatitis (APD) are generally non-specific and have been described only in brief case reports. We present a case of APD and review the literature with a focus on the histologic findings described. A review of the English literature on APD was performed using PubMed and MEDLINE. A total of 39 patients, including our patient are included in this review. The most consistent histologic finding reported was a perivascular inflammatory infiltrate, being seen in 72% of cases. A non-specific or interstitial inflammatory infiltrate was described in 31% of the cases, with 41% having an eosinophilic component and 21% having a neutrophilic component mixed with the predominant lymphocytic infiltrate. Interface dermatitis was the second most common finding with 36% showing a mild to exaggerated interface dermatitis. Although histopathologic changes are non-specific, perivascular dermatitis with eosinophils and interface changes are common in APD. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Environmental Radiation Measurements on MIR Station. Program 1; Internal Experiment
NASA Technical Reports Server (NTRS)
Benton, E. V.; Frank, A. L.; Benton, E. R.
1997-01-01
Environmental radiation levels on the Russian space station Mir are being monitored under differing shielding conditions by a series of six area passive dosimeters (APDs) placed at individual locations inside the Core and Kvant 2 modules, and by an External Dosimeter Array (EDA) to be-deployed on the exterior surface of the Kvant 2 module. Each APD and the EDA contains CR-39 plastic nuclear track detectors (PNTDs) for measurement of LET spectra and TLDs for absorbed dose measurements. Two of the missions, NASA-2/Mir-21 and NASA-3/Mir-22 have been completed and the six APDs from each mission returned to Earth from Mir. This report covers progress to date on the analysis of TLDs and PNTDs from these two missions. For NASA-2/Mir-21, average mission absorbed dose rates varied from 271 to 407 micro-Gy/d at the APDS. For NASA-3/Mir-22, average mission absorbed dose rates varied from 265 to 421 micro-Gy/d.
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Cognitive control deficits associated with antisocial personality disorder and psychopathy.
Zeier, Joshua D; Baskin-Sommers, Arielle R; Hiatt Racer, Kristina D; Newman, Joseph P
2012-07-01
Antisociality has been linked to a variety of executive functioning deficits, including poor cognitive control. Surprisingly, cognitive control deficits are rarely found in psychopathic individuals, despite their notoriously severe and persistent antisocial behavior. In fact, primary (low-anxious) psychopathic individuals display superior performance on cognitive control-type tasks under certain circumstances. To clarify these seemingly contradictory findings, we administered a response competition (i.e., flanker) task to incarcerated offenders, who were assessed for Antisocial Personality Disorder (APD) symptoms and psychopathy. As hypothesized, APD related to poorer accuracy, especially on incongruent trials. Contrary to expectation, however, the same pattern of results was found in psychopathy. Additional analyses indicated that these effects of APD and psychopathy were associated with overlapping variance. The findings suggest that psychopathy and APD symptoms are both associated with deficits in cognitive control, and that this deficit relates to general antisociality as opposed to a specific antisocial syndrome. PsycINFO Database Record (c) 2012 APA, all rights reserved.
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NASA Astrophysics Data System (ADS)
Roberts, Peter M.
The purpose of this study was to examine white noise effects of U.S. crude oil spot prices on the stock prices of a green energy company. Epistemological, Phenomenological, Axiological and Ontological assumptions of Green Energy Management (GEM) Theory were utilized for selecting Air Products and Chemicals Inc. (APD) as the case study. Exxon Mobil (XOM) was used as a control for triangulation purposes. The period of time examined was between January of 1999 and December of 2008. Monthly stock prices for APD and XOM for the ten year period of time were collected from the New York Stock Exchange. Monthly U.S. crude oil spot prices for the ten year period of time were collected from the US Energy Information Administration. The data was entered into SPSS 17.0 software in order to conduct cross-correlation analysis. The six cross-correlation assumptions were satisfied in order to conduct a Cross-correlation Mirror Test (CCMT). The CCMT established the lag time direction and verified that U.S. crude oil spot prices serve as white noise for stock prices of APD and XOM. The Theory of Relative Weakness was employed in order to analyze the results. A 2 year period of time between December, 2006 and December, 2008 was examined. The correlation coefficient r = - .155 indicates that U.S. crude oil spot prices lead APD stock prices by 4 months. During the same 2 year period of time, U.S. crude oil spot prices lead XOM stock prices by 4 months at r = -.283. XOM stock prices and APD stock prices were positively correlated with 0 lag in time with a positive r = .566. The 4 month cycle was an exact match between APD stock prices, XOM stock prices and U.S. crude oil spot prices. The 4 month cycle was due to the random price fluctuation of U.S. crude oil spot prices that obscured the true stock prices of APD and XOM for the 2 year period of time.
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Efficient entanglement distribution over 200 kilometers.
Dynes, J F; Takesue, H; Yuan, Z L; Sharpe, A W; Harada, K; Honjo, T; Kamada, H; Tadanaga, O; Nishida, Y; Asobe, M; Shields, A J
2009-07-06
Here we report the first demonstration of entanglement distribution over a record distance of 200 km which is of sufficient fidelity to realize secure communication. In contrast to previous entanglement distribution schemes, we use detection elements based on practical avalanche photodiodes (APDs) operating in a self-differencing mode. These APDs are low-cost, compact and easy to operate requiring only electrical cooling to achieve high single photon detection efficiency. The self-differencing APDs in combination with a reliable parametric down-conversion source demonstrate that entanglement distribution over ultra-long distances has become both possible and practical. Consequently the outlook is extremely promising for real world entanglement-based communication between distantly separated parties.
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Auditory Processing Disorders: Acquisition and Treatment
ERIC Educational Resources Information Center
Moore, David R.
2007-01-01
Auditory processing disorder (APD) describes a mixed and poorly understood listening problem characterised by poor speech perception, especially in challenging environments. APD may include an inherited component, and this may be major, but studies reviewed here of children with long-term otitis media with effusion (OME) provide strong evidence…
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Code of Federal Regulations, 2010 CFR
2010-10-01
... Equipment and Services-Conditions for Federal Financial Participation (FFP) General § 95.605 Definitions. As... acquiring ADP equipment or services from commercial sources or from State or local government resources... use of ADP services or equipment. The term APD refers to a Planning APD, or to a planning and/or...
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Akiba, M., E-mail: akiba@nict.go.jp; Tsujino, K.
This paper offers a theoretical explanation of the temperature and temporal dependencies of transient dark count rates (DCRs) measured for a linear-mode silicon avalanche photodiode (APD) and the dependencies of afterpulsing that were measured in Geiger-mode Si and InGaAs/InP APDs. The temporal dependencies exhibit power-law behavior, at least to some extent. For the transient DCR, the value of the DCR for a given time period increases with decreases in temperature, while the power-law behavior remains unchanged. The transient DCR is attributed to electron emissions from traps in the multiplication layer of the APD with a high electric field, and itsmore » temporal dependence is explained by a continuous change in the electron emission rate as a function of the electric field strength. The electron emission rate is calculated using a quantum model for phonon-assisted tunnel emission. We applied the theory to the temporal dependence of afterpulsing that was measured for Si and InGaAs/InP APDs. The power-law temporal dependence is attributed to the power-law function of the electron emission rate from the traps as a function of their position across the p–n junction of the APD. Deviations from the power-law temporal dependence can be derived from the upper and lower limits of the electric field strength.« less
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FACT - Status and experience from five years of operation of the first G-APD Cherenkov Telescope
NASA Astrophysics Data System (ADS)
Neise, D.; Adam, J.; Ahnen, M. L.; Baack, D.; Balbo, M.; Bergmann, M.; Biland, A.; Blank, M.; Bretz, T.; Brügge, K. A.; Buss, J.; Dmytriiev, A.; Dorner, D.; Einecke, S.; Hempfling, C.; Hildebrand, D.; Hughes, G.; Linhoff, L.; Mannheim, K.; Müller, S.; Neronov, A.; Nöthe, M.; Paravac, A.; Pauss, F.; Rhode, W.; Shukla, A.; Temme, F.; Thaele, J.; Walter, R.
2017-12-01
The First G-APD Cherenkov Telescope (FACT) demonstrates the usability of novel Geiger-mode operated Avalanche Photo Diodes (G-APD, often called SiPM) for Imaging Atmospheric Cherenkov Telescopes (IACT). The camera consists of 1440 pixels with dedicated electronics operating at 2 Giga samples per second. It is installed on the refurbished HEGRA telescope with a mirror area of ≈ 9.5m2 on the Canary Island La Palma. FACT is taking data almost every night since the camera was installed in October 2011. It was possible to improve the data taking efficiency to very high values due to the very stable and reliable operation. This also allows to operate FACT remotely without any need for operators on site. Even remote human intervention became less and less frequent over the years, allowing operation to become mostly automatic. FACT is monitoring the long-term behavior of some very-high energy variable extra-galactic sources with unparalleled sampling density as well as testing the behavior of the sensors under severe weather conditions. Due to the long exposure of FACT's G-APDs under strong moonlight conditions it was possible to evaluate the aging effects of G-APDs due to collected charge. No indication of aging was found. No external calibration device is needed to operate FACT since the properties of the sensors themselves allow for a high precision self-calibration of the camera.
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Ultra-violet avalanche photodiode based on AlN/GaN periodically-stacked-structure
NASA Astrophysics Data System (ADS)
Wu, Xingzhao; Zheng, Jiyuan; Wang, Lai; Brault, Julien; Matta, Samuel; Hao, Zhibiao; Sun, Changzheng; Xiong, Bing; Luo, Yi; Han, Yianjun; Wang, Jian; Li, Hongtao; Khalfioui, Mohamed A.; Li, Mo; Kang, Jianbin; Li, Qian
2018-02-01
The high-gain photomultiplier tube (PMT) is the most popular method to detect weak ultra-violet signals which attenuate quickly in atmosphere, although the vacuum tube makes it fragile and difficult to integrate. To overcome the disadvantage of PMT, an AlN/GaN periodically-stacked-structure (PSS) avalanche photodiode (APD) has been proposed, finally achieving good quality of high gain and low excessive noise. As there is a deep g valley only in the conduction band of both GaN and AlN, the electron transfers suffering less scattering and thus becomes easier to obtain the threshold of ionization impact. Because of unipolar ionization in the PSS APD, it works in linear mode. Four prototype devices of 5-period, 10-period, 15-period, and 20-period were fabricated to verify that the gain of APD increases exponentially with period number. And in 20-period device, a recorded high and stable gain of 104 was achieved under constant bias. In addition, it is proved both experimentally and theoretically, that temperature stability on gain is significantly improved in PSS APD. And it is found that the resonant enhancement in interfacial ionization may bring significant enhancement of electron ionization performance. To make further progress in PSS APD, the device structure is investigated by simulation. Both the gain and temperature stability are optimized alternatively by a proper design of periodical thickness and AlN layer occupancy.
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Kumari, Veena; Das, Mrigen; Hodgins, Sheilagh; Zachariah, Elizabeth; Barkataki, Ian; Howlett, Michael; Sharma, Tonmoy
2005-03-07
Violent behaviour has a strong association with antisocial personality disorder (APD) and schizophrenia. Although developments in the understanding of socio-environmental factors associated with violence should not be ignored, advances in prevention and treatment of violent behaviour would benefit by improved understanding of its neurobiological and cognitive basis. The authors, therefore, investigated prepulse inhibition (PPI) of the startle response in APD and schizophrenia in relation to a history of serious violence. The neural substrates of PPI, especially the hippocampus, amygdala, thalamus and basal ganglia, are implicated in violence as well as in APD and schizophrenia. The study included four groups: (i) patients with APD and a history of violence, (ii) patients with schizophrenia and a history of violence, (iii) patients with schizophrenia without a history of violence, and (iv) healthy subjects with no history of violence or a mental disorder. All subjects were assessed identically on acoustic PPI. Compared to healthy subjects, significantly reduced PPI occurred in APD, violent schizophrenia and non-violent schizophrenia patients. Although PPI did not significantly differentiate the three clinical groups, high ratings of violence were modestly associated with reduced PPI across the entire study sample. Violent patients with impulsive and premeditated violence showed comparable PPI. The association between violent behaviour and impaired PPI suggests that neural structures and functions underlying PPI are implicated in (inhibition of) violence.
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Comorbidity of Auditory Processing, Language, and Reading Disorders
ERIC Educational Resources Information Center
Sharma, Mridula; Purdy, Suzanne C.; Kelly, Andrea S.
2009-01-01
Purpose: The authors assessed comorbidity of auditory processing disorder (APD), language impairment (LI), and reading disorder (RD) in school-age children. Method: Children (N = 68) with suspected APD and nonverbal IQ standard scores of 80 or more were assessed using auditory, language, reading, attention, and memory measures. Auditory processing…
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Peeling the Onion of Auditory Processing Disorder: A Language/Curricular-Based Perspective
ERIC Educational Resources Information Center
Wallach, Geraldine P.
2011-01-01
Purpose: This article addresses auditory processing disorder (APD) from a language-based perspective. The author asks speech-language pathologists to evaluate the functionality (or not) of APD as a diagnostic category for children and adolescents with language-learning and academic difficulties. Suggestions are offered from a…
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45 CFR 307.15 - Approval of advance planning documents for computerized support enforcement systems.
Code of Federal Regulations, 2014 CFR
2014-10-01
... CHILDREN AND FAMILIES, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPUTERIZED SUPPORT ENFORCEMENT SYSTEMS..., organization, services and constraints related to the computerized support enforcement system; (4) The APD must... design, development, installation or enhancement; (5) The APD must contain a description of each...
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45 CFR 307.15 - Approval of advance planning documents for computerized support enforcement systems.
Code of Federal Regulations, 2013 CFR
2013-10-01
... CHILDREN AND FAMILIES, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPUTERIZED SUPPORT ENFORCEMENT SYSTEMS..., organization, services and constraints related to the computerized support enforcement system; (4) The APD must... design, development, installation or enhancement; (5) The APD must contain a description of each...
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45 CFR 307.15 - Approval of advance planning documents for computerized support enforcement systems.
Code of Federal Regulations, 2012 CFR
2012-10-01
... CHILDREN AND FAMILIES, DEPARTMENT OF HEALTH AND HUMAN SERVICES COMPUTERIZED SUPPORT ENFORCEMENT SYSTEMS..., organization, services and constraints related to the computerized support enforcement system; (4) The APD must... design, development, installation or enhancement; (5) The APD must contain a description of each...
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Thomson Scattering Diagnostic Data Acquisition Systems for Modern Fusion Systems
DOE Office of Scientific and Technical Information (OSTI.GOV)
Ivanenko, S.V.; Khilchenko, A.D.; Ovchar, V.K.
2015-07-01
Uniquely designed complex data acquisition system for Thomson scattering diagnostic was developed. It allows recording short duration (3-5 ns) scattered pulses with 2 GHz sampling rate and 10-bit total resolution in oscilloscope mode. The system consists up to 48 photo detector modules with 0- 200 MHz bandwidth, 1-48 simultaneously sampling ADC modules and synchronization subsystem. The photo detector modules are based on avalanche photodiodes (APD) and ultra-low noise trans-impedance amplifiers. ADC modules include fast analog to digital converters and digital units based on the FPGA (Field- Programmable Gate Array) for data processing and storage. The synchronization subsystem is used tomore » form triggering pulses and to organize the simultaneously mode of ADC modules operation. (authors)« less
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Zhan, He-qing; Xia, Ling; Shou, Guo-fa; Zang, Yun-liang; Liu, Feng; Crozier, Stuart
2014-03-01
In this study, the effects of cardiac fibroblast proliferation on cardiac electric excitation conduction and mechanical contraction were investigated using a proposed integrated myocardial-fibroblastic electromechanical model. At the cellular level, models of the human ventricular myocyte and fibroblast were modified to incorporate a model of cardiac mechanical contraction and cooperativity mechanisms. Cellular electromechanical coupling was realized with a calcium buffer. At the tissue level, electrical excitation conduction was coupled to an elastic mechanics model in which the finite difference method (FDM) was used to solve electrical excitation equations, and the finite element method (FEM) was used to solve mechanics equations. The electromechanical properties of the proposed integrated model were investigated in one or two dimensions under normal and ischemic pathological conditions. Fibroblast proliferation slowed wave propagation, induced a conduction block, decreased strains in the fibroblast proliferous tissue, and increased dispersions in depolarization, repolarization, and action potential duration (APD). It also distorted the wave-front, leading to the initiation and maintenance of re-entry, and resulted in a sustained contraction in the proliferous areas. This study demonstrated the important role that fibroblast proliferation plays in modulating cardiac electromechanical behaviour and which should be considered in planning future heart-modeling studies.
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Zhan, He-qing; Xia, Ling; Shou, Guo-fa; Zang, Yun-liang; Liu, Feng; Crozier, Stuart
2014-01-01
In this study, the effects of cardiac fibroblast proliferation on cardiac electric excitation conduction and mechanical contraction were investigated using a proposed integrated myocardial-fibroblastic electromechanical model. At the cellular level, models of the human ventricular myocyte and fibroblast were modified to incorporate a model of cardiac mechanical contraction and cooperativity mechanisms. Cellular electromechanical coupling was realized with a calcium buffer. At the tissue level, electrical excitation conduction was coupled to an elastic mechanics model in which the finite difference method (FDM) was used to solve electrical excitation equations, and the finite element method (FEM) was used to solve mechanics equations. The electromechanical properties of the proposed integrated model were investigated in one or two dimensions under normal and ischemic pathological conditions. Fibroblast proliferation slowed wave propagation, induced a conduction block, decreased strains in the fibroblast proliferous tissue, and increased dispersions in depolarization, repolarization, and action potential duration (APD). It also distorted the wave-front, leading to the initiation and maintenance of re-entry, and resulted in a sustained contraction in the proliferous areas. This study demonstrated the important role that fibroblast proliferation plays in modulating cardiac electromechanical behaviour and which should be considered in planning future heart-modeling studies. PMID:24599687
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Kishimoto, Shunji; Zhang Xiaowei; Yoda, Yoshitaka
2007-01-19
A timing detector with silicon avalanche photodiodes (Si-APDs) has been developed for nuclear resonant scattering using synchrotron x-rays. The detector had four pairs of a germanium plate 0.1mm thick and a Si-APD (3 mm in dia., a depletion layer of 30-{mu}m thickness). Using synchrotron x-rays of 67.4 keV, the efficiency increased to 1.5% for the incident beam, while the efficiency was 0.76 % without the germanium converters. A measurement of SR-PAC on Ni-61 was executed by using the detector. Some other types of timing detectors are planned for x-rays of E>20 keV.
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Performance enhancement of GaN ultraviolet avalanche photodiodes with p-type δ-doping
NASA Astrophysics Data System (ADS)
Bayram, C.; Pau, J. L.; McClintock, R.; Razeghi, M.
2008-06-01
High quality δ-doped p-GaN is used as a means of improving the performance of back-illuminated GaN avalanche photodiodes (APDs). Devices with δ-doped p-GaN show consistently lower leakage current and lower breakdown voltage than those with bulk p-GaN. APDs with δ-doped p-GaN also achieve a maximum multiplication gain of 5.1×104, more than 50 times higher than that obtained in devices with bulk p-GaN. The better device performance of APDs with δ-doped p-GaN is attributed to the higher structural quality of the p-GaN layer achieved via δ-doping.
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AlInAsSb separate absorption, charge, and multiplication avalanche photodiodes
NASA Astrophysics Data System (ADS)
Ren, Min; Maddox, Scott J.; Woodson, Madison E.; Chen, Yaojia; Bank, Seth R.; Campbell, Joe C.
2016-05-01
We report AlxIn1-xAsySb1-y separate absorption, charge, and multiplication avalanche photodiodes (APDs) that operate in the short-wavelength infrared spectrum. They exhibit excess noise factor less or equal to that of Si and the low dark currents typical of III-V compound APDs.
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45 CFR 1355.56 - Failure to meet the conditions of the approved APD.
Code of Federal Regulations, 2012 CFR
2012-10-01
... 45 Public Welfare 4 2012-10-01 2012-10-01 false Failure to meet the conditions of the approved APD. 1355.56 Section 1355.56 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF..., YOUTH AND FAMILIES, FOSTER CARE MAINTENANCE PAYMENTS, ADOPTION ASSISTANCE, AND CHILD AND FAMILY SERVICES...
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45 CFR 1355.56 - Failure to meet the conditions of the approved APD.
Code of Federal Regulations, 2014 CFR
2014-10-01
... 45 Public Welfare 4 2014-10-01 2014-10-01 false Failure to meet the conditions of the approved APD. 1355.56 Section 1355.56 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF..., YOUTH AND FAMILIES, FOSTER CARE MAINTENANCE PAYMENTS, ADOPTION ASSISTANCE, AND CHILD AND FAMILY SERVICES...
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45 CFR 1355.56 - Failure to meet the conditions of the approved APD.
Code of Federal Regulations, 2011 CFR
2011-10-01
... 45 Public Welfare 4 2011-10-01 2011-10-01 false Failure to meet the conditions of the approved APD. 1355.56 Section 1355.56 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF..., YOUTH AND FAMILIES, FOSTER CARE MAINTENANCE PAYMENTS, ADOPTION ASSISTANCE, AND CHILD AND FAMILY SERVICES...
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Magnetic Properties and Moessbauer Spectra of Several Iron(III) Dicarboxylic Acid Complexes.
1980-10-01
model CS-202 Displex Cryogenic refrigerator with a model APD-E temperature controller manufactured by Air Products and Chemicals , Inc ., Allentown, Pa...coupled tL a special, helium gas filled shroud, Model DMX-20, supplied by Air Products and Chemicals , Inc . Infrared spectra were obtained on a Beckman IR
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ERIC Educational Resources Information Center
Maerlender, Arthur
2010-01-01
Auditory processing disorders (APDs) are of interest to educators and clinicians, as they impact school functioning. Little work has been completed to demonstrate how children with APDs perform on clinical tests. In a series of studies, standard clinical (psychometric) tests from the Wechsler Intelligence Scale for Children, Fourth Edition…
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Predicting Future Antisocial Personality Disorder in Males from a Clinical Assessment in Childhood
ERIC Educational Resources Information Center
Lahey, Benjamin B.; Loeber, Rolf; Burke, Jeffrey D.; Applegate, Brooks
2005-01-01
It is essential to identify childhood predictors of adult antisocial personality disorder (APD) to target early prevention. It has variously been hypothesized that APD is predicted by childhood conduct disorder (CD), attention-deficit/hyperactivity disorder (ADHD), or both disorders. To test these competing hypotheses, the authors used data from a…
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Wang, Xiaodong; Pan, Ming; Hou, Liwei
2014-01-07
The gain and photoresponse characteristics have been numerically studied for back-illuminated separate absorption and multiplication (SAM) GaN avalanche photodiodes (APDs). The parameters of fundamental models are calibrated by simultaneously comparing the simulated dark and light current characteristics with the experimental results. Effects of environmental temperatures and device dimensions on gain characteristics have been investigated, and a method to achieve the optimum thickness of charge layer is obtained. The dependence of gain characteristics and breakdown voltage on the doping concentration of the charge layer is also studied in detail to get the optimal charge layer. The bias-dependent spectral responsivity and quantummore » efficiency are then presented to study the photoresponse mechanisms inside SAM GaN APDs. It is found the responsivity peak red-shifts at first due to the Franz-Keldysh effect and then blue-shifts due to the reach-through effect of the absorption layer. Finally, a new SAM GaN/AlGaN heterojunction APD structure is proposed for optimizing SAM GaN APDs.« less
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Yun, Ruida; Sthalekar, Chirag; Joyner, Valencia M
2011-01-01
This paper presents the design and measurement results of two avalanche photodiode structures (APDs) and a novel frequency-mixing transimpedance amplifier (TIA), which are key building blocks towards a monolithically integrated optical sensor front end for near-infrared (NIR) spectroscopy applications. Two different APD structures are fabricated in an unmodified 0.18 \\im CMOS process, one with a shallow trench isolation (STI) guard ring and the other with a P-well guard ring. The APDs are characterized in linear mode. The STI bounded APD demonstrates better performance and exhibits 3.78 A/W responsivity at a wavelength of 690 nm and bias voltage of 10.55 V. The frequency-mixing TIA (FM-TIA) employs a T-feedback network incorporating gate-controlled transistors for resistance modulation, enabling the simultaneous down-conversion and amplification of the high frequency modulated photodiode (PD) current. The TIA achieves 92 dS Ω conversion gain with 0.5 V modulating voltage. The measured IIP(3) is 10.6/M. The amplifier together with the 50 Ω output buffer draws 23 mA from a1.8 V power supply.
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Chan, Chung-Hung; See, Tiam-You; Yusoff, Rozita; Ngoh, Gek-Cheng; Kow, Kien-Woh
2017-04-15
This work demonstrated the optimization and scale up of microwave-assisted extraction (MAE) and ultrasonic-assisted extraction (UAE) of bioactive compounds from Orthosiphon stamineus using energy-based parameters such as absorbed power density and absorbed energy density (APD-AED) and response surface methodology (RSM). The intensive optimum conditions of MAE obtained at 80% EtOH, 50mL/g, APD of 0.35W/mL, AED of 250J/mL can be used to determine the optimum conditions of the scale-dependent parameters i.e. microwave power and treatment time at various extraction scales (100-300mL solvent loading). The yields of the up scaled conditions were consistent with less than 8% discrepancy and they were about 91-98% of the Soxhlet extraction yield. By adapting APD-AED method in the case of UAE, the intensive optimum conditions of the extraction, i.e. 70% EtOH, 30mL/g, APD of 0.22W/mL, AED of 450J/mL are able to achieve similar scale up results. Copyright © 2016 Elsevier Ltd. All rights reserved.
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The 1.06 optical receiver. [avalanche photodiodes for laser range finders
NASA Technical Reports Server (NTRS)
Tomasetta, L. R.; Law, H. D.; Nakano, K.; Scholl, F. W.; Harris, J. S., Jr.
1978-01-01
High performance 1.06 micron m avalanche photodetectors (APDs), fabricated in the GaAlSb system, have high quantum efficiency (90 percent), high speed (risetime less than 60 ps) and low leakage currents (less than 50 na). The dark current represents more than an order of magnitude reduction compared to previously reported results. The high speed avalanche gain of these devices is between 20 and 50. The area uniformity is better than + or - 10 percent. GaAlAs APDs at 0.53 micron m have even faster speed, lower dark currents, and high speed gains of 100 to 200. Optical rangefinders based on measured APD performance parameters have far superior performance when compared to even ideal photomultiplier tubes in either a one color or two color rangefinder system. For a one color system, f factor of two lower time jitter can be achieved with identical transmitted power. The superiority of the APD based two color receiver is significant and exists in the entire range of desired time jitters (less than 100 ps) and received power levels.
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Characterization of Geiger mode avalanche photodiodes for fluorescence decay measurements
NASA Astrophysics Data System (ADS)
Jackson, John C.; Phelan, Don; Morrison, Alan P.; Redfern, R. Michael; Mathewson, Alan
2002-05-01
Geiger mode avalanche photodiodes (APD) can be biased above the breakdown voltage to allow detection of single photons. Because of the increase in quantum efficiency, magnetic field immunity, robustness, longer operating lifetime and reduction in costs, solid-state detectors capable of operating at non-cryogenic temperatures and providing single photon detection capabilities provide attractive alternatives to the photomultiplier tube (PMT). Shallow junction Geiger mode APD detectors provide the ability to manufacture photon detectors and detector arrays with CMOS compatible processing steps and allows the use of novel Silicon-on-Insulator(SoI) technology to provide future integrated sensing solutions. Previous work on Geiger mode APD detectors has focused on increasing the active area of the detector to make it more PMT like, easing the integration of discrete reaction, detection and signal processing into laboratory experimental systems. This discrete model for single photon detection works well for laboratory sized test and measurement equipment, however the move towards microfluidics and systems on a chip requires integrated sensing solutions. As we move towards providing integrated functionality of increasingly nanoscopic sized emissions, small area detectors and detector arrays that can be easily integrated into marketable systems, with sensitive small area single photon counting detectors will be needed. This paper will demonstrate the 2-dimensional and 3-dimensional simulation of optical coupling that occurs in Geiger mode APDs. Fabricated Geiger mode APD detectors optimized for fluorescence decay measurements were characterized and preliminary results show excellent results for their integration into fluorescence decay measurement systems.
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Advanced Parkinson disease patients have impairment in prosody processing.
Albuquerque, Luisa; Martins, Maurício; Coelho, Miguel; Guedes, Leonor; Ferreira, Joaquim J; Rosa, Mário; Martins, Isabel Pavão
2016-01-01
The ability to recognize and interpret emotions in others is a crucial prerequisite of adequate social behavior. Impairments in emotion processing have been reported from the early stages of Parkinson's disease (PD). This study aims to characterize emotion recognition in advanced Parkinson's disease (APD) candidates for deep-brain stimulation and to compare emotion recognition abilities in visual and auditory domains. APD patients, defined as those with levodopa-induced motor complications (N = 42), and healthy controls (N = 43) matched by gender, age, and educational level, undertook the Comprehensive Affect Testing System (CATS), a battery that evaluates recognition of seven basic emotions (happiness, sadness, anger, fear, surprise, disgust, and neutral) on facial expressions and four emotions on prosody (happiness, sadness, anger, and fear). APD patients were assessed during the "ON" state. Group performance was compared with independent-samples t tests. Compared to controls, APD had significantly lower scores on the discrimination and naming of emotions in prosody, and visual discrimination of neutral faces, but no significant differences in visual emotional tasks. The contrasting performance in emotional processing between visual and auditory stimuli suggests that APD candidates for surgery have either a selective difficulty in recognizing emotions in prosody or a general defect in prosody processing. Studies investigating early-stage PD, and the effect of subcortical lesions in prosody processing, favor the latter interpretation. Further research is needed to understand these deficits in emotional prosody recognition and their possible contribution to later behavioral or neuropsychiatric manifestations of PD.
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Bérard, P; Bergeron, M; Pepin, C M; Cadorette, J; Tétrault, M-A; Viscogliosi, N; Fontaine, R; Dautet, H; Davies, M; Lecomte, R
2008-07-01
Visualization and quantification of biological processes in mice, the preferred animal model in most preclinical studies, require the best possible spatial resolution in positron emission tomography (PET). A new 64-channel avalanche photodiode (APD) detector module was developed to achieve submillimeter spatial resolution for this purpose. The module consists of dual 4 × 8 APD arrays mounted in a custom ceramic holder. Individual APD pixels having an active area of 1.1 × 1.1 mm2 at a 1.2 mm pitch can be fitted to an 8 × 8 LYSO scintillator block designed to accommodate one-to-one coupling. An analog test board with four 16-channel preamplifier ASICs was designed to be interfaced with the existing LabPET digital processing electronics. At a standard APD operating bias, a mean energy resolution of 27.5 ± 0.6% was typically obtained at 511 keV with a relative standard deviation of 13.8% in signal amplitude for the 64 individual pixels. Crosstalk between pixels was found to be well below the typical lower energy threshold used for PET imaging applications. With two modules in coincidence, a global timing resolution of 5.0 ns FWHM was measured. Finally, an intrinsic spatial resolution of 0.8 mm FWHM was measured by sweeping a 22Na point source between two detector arrays. The proposed detector module demonstrates promising characteristics for dedicated mouse PET imaging at submillimiter resolution. © 2008 American Association of Physicists in Medicine.
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Costs of home assistance for peritoneal dialysis: results of a European survey.
Dratwa, M
2008-04-01
Assisted peritoneal dialysis (aPD) was 'invented' in France in 1977 and was immediately very well reimbursed. This has since helped to maintain a high French peritoneal dialysis (PD) penetration rate among elderly dependent patients who might enjoy a better quality of life by remaining in their own environment. The aim of this study was to investigate the present status of aPD funding in European countries through a questionnaire sent in 2006 to health authorities and commercial PD providers asking about reimbursement modalities (in euro ([euro]) per patient per year) for nurse aPD. Specific funding for aPD only exists in Belgium, Denmark, France, Switzerland, and one region of Spain (Canary Islands). Germany and the United Kingdom are testing pilot schemes. Compared to France, all other countries exhibit significant differences in reimbursement for similar services (performing bag exchanges or disconnections from/to a cycler, exit site care, monitoring weight as well as blood pressure and ultrafiltration, and also including transportation costs) both for continuous ambulatory peritoneal dialysis (CAPD) (23 400 vs 7280 \\[euro] per patient per year in Spain) and automated peritoneal dialysis (APD) (18 200 vs 5356 euro per patient per year in Belgium); these differences are difficult to understand and might reflect disparities in cost of living, national health-care budget, and/or mean nurses' salaries. Also, there is no correlation between these rates and the reimbursement for PD therapy itself. Only France and Belgium differentiate assisted CAPD and APD, but these differences do not reflect the time really spent at the patient's home. It is concluded that high reimbursement rates for assistance add significant extra cost to PD, but allow granting many dependent patients all the advantages of home therapy, instead of treating them with in-center hemodialysis which in any case still remains more expensive for our societies.
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Majumder, Rupamanjari; Jangsangthong, Wanchana; Feola, Iolanda; Ypey, Dirk L.; Pijnappels, Daniël A.; Panfilov, Alexander V.
2016-01-01
Atrial fibrillation (AF) is the most frequent form of arrhythmia occurring in the industrialized world. Because of its complex nature, each identified form of AF requires specialized treatment. Thus, an in-depth understanding of the bases of these arrhythmias is essential for therapeutic development. A variety of experimental studies aimed at understanding the mechanisms of AF are performed using primary cultures of neonatal rat atrial cardiomyocytes (NRAMs). Previously, we have shown that the distinct advantage of NRAM cultures is that they allow standardized, systematic, robust re-entry induction in the presence of a constitutively-active acetylcholine-mediated K+ current (IKACh-c). Experimental studies dedicated to mechanistic explorations of AF, using these cultures, often use computer models for detailed electrophysiological investigations. However, currently, no mathematical model for NRAMs is available. Therefore, in the present study we propose the first model for the action potential (AP) of a NRAM with constitutively-active acetylcholine-mediated K+ current (IKACh-c). The descriptions of the ionic currents were based on patch-clamp data obtained from neonatal rats. Our monolayer model closely mimics the action potential duration (APD) restitution and conduction velocity (CV) restitution curves presented in our previous in vitro studies. In addition, the model reproduces the experimentally observed dynamics of spiral wave rotation, in the absence and in the presence of drug interventions, and in the presence of localized myofibroblast heterogeneities. PMID:27332890
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Kontessis, P A; Bossinakou, I; Sarika, L; Iliopoulou, E; Papantoniou, A; Trevisan, R; Roussi, D; Stipsanelli, K; Grigorakis, S; Souvatzoglou, A
1995-09-01
Whether the differences in renal function found in vegetarian compared with omnivorous subjects are related to quantity or quality of the protein is unknown. We have studied the renal function of nine normotensive, nonproteinuric type I diabetic patients who were fed in random order for 4 weeks either an animal protein diet (APD) (protein intake 1.1 g . kg-1 . day-1) or a vegetable protein diet VPD (protein intake 0.95 g . kg-1 . day-1). The two diets were isocaloric. In a crossover study, we measured glomerular filtration rate (GFR) (inulin clearance), renal plasma flow (RPF) (p-aminohippurate clearance), plasma amino acids, growth hormone, glucagon, insulin-like growth factor I-(IGF-I), and microalbuminuria. GFR and RPF were lower with the VPD than with the APD (89.9 +/- 4.1 vs. 105.6 +/- 5.1 ml . min-1 . 1.73 m-2, P < 0.05, and 425.7 +/- 22.2 vs. 477.8 +/- 32.2 ml . min-1 1.73m-2, P < 0.05, respectively). Renal vascular resistance (RVR) was higher with the VPD than with the APD (101 +/- 25 vs. 91 +/- 10 mmHg . min-1 . ml-1, P < 0.05). Filtration fraction (FF) remained unchanged after either diet. Fractional clearance of albumin fell with the VPD to 2.0 +/- 0.65 from 3.4 +/- 1.15 x 10-6 (P < 0.05). At the end of the APD and VPD, the plasma levels of growth hormone and glucagon did not differ significantly. Plasma levels of IGF-I were higher with the APD than with the VPD (1.1 +/- 0.6 vs. 0.9 +/- 0.13 U/ml, P < 0.05). Plasma concentrations of valine and lysine were significantly higher with the APD than with the VPD (234.6 +/- 30.3 vs. 164.5 +/- 25.4 mm1/1, P < 0.05, and 565 +/- 45.1 vs. 430 +/- 56.1 mmol/l, P < 0.05, respectively), whereas plasma valine was strongly correlated to the GFR (r = 0.832, P < 0.01). No differences were found in other amino acids. A VPD has significantly different renal effects from an APD equal in protein intake in normotensive type I diabetic patients. This could be explained partly by differences in plasma concentrations of amino acids and IGF-I.
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Aktaş, Gul Ege; Sarıkaya, Ali
2015-11-01
Children with unilateral hydronephrosis are followed up with anteroposterior pelvic diameter (APD), hydronephrosis grade, mercaptoacetyltriglycine (MAG-3) drainage pattern and differential renal function (DRF). Indeterminate drainage preserved DRF in higher grades of hydronephrosis, in some situations, complicating the decision-making process. Due to an asymmetric renal area ratio, falsely negative DRF estimations can result in missed optimal surgery times. This study was designed to assess whether correcting the DRF estimation according to kidney area could reflect the clinical situation of a hydronephrotic kidney better than a classical DRF calculation, concurrently with the hydronephrosis grade, APD and MAG-3 drainage pattern. We reviewed the MAG-3, dimercaptosuccinic acid (DMSA) scans and ultrasonography (US) of 23 children (6 girls, 17 boys, mean age: 29 ± 50 months) with unilateral hydronephrosis. MAG-3 and DMSA scans were performed within 3 months (mean 25.4 ± 30.7 days). The closest US findings (mean 41.5 ± 28.2 days) were used. DMSA DRF estimations were obtained using the geometric mean method. Secondary calculations were performed to correct the counts (the total counts divided by the number of pixels in ROI) according to kidney area. The renogram patterns of patients were evaluated and separated into subgroups. The visual assessment of DMSA scans was noted and the hydronephrotic kidney was classified in comparison to the normal contralateral kidney's uptake. The correlations of the DRF values of classical and area-corrected methods with MAG-3 renogram patterns, the visual classification of DMSA scan, the hydronephrosis grade and the APD were assessed. DRF estimations of two methods were statistically different (p: 0.001). The categories of 12 hydronephrotic kidneys were changed. There were no correlations between classical DRF estimations and the hydronephrosis grade, APD, visual classification of the DMSA scan and uptake evaluation. The DRF distributions according to MAG-3 drainage patterns were not different. Area-corrected DRF estimations correlated with all: with an increasing hydronephrosis grade and APD, DRF estimations decreased and MAG-3 drainage patterns worsened. A decrease in DRF (< 45 %) was determined when APD was ≥ 10 mm. When APD was ≥ 26 mm, a reduction of DRF below 40 % was determined. Our results suggest that correcting DRF estimation for asymmetric renal area ratio in unilateral hydronephrosis can be more robust than the classical method, especially for higher grades of hydronephrotic kidneys, under equivocal circumstances.
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Di Pietro, N C; Seamans, J K
2007-12-01
Diminished activity within the prefrontal cortex (PFC) has been associated with many of the cognitive deficits that are observed in schizophrenia. It has been hypothesized that antipsychotic drugs (APDs) used to treat schizophrenia restore normal activity by antagonizing the dopamine (DA) D2 receptor, which is also known to modulate key ionic currents in the PFC. However, the hypothesis that an under-active cortical DA system is responsible for schizophrenic symptoms has been challenged by evidence that newer atypical APDs are weak antagonists at the D2 receptor but potent antagonists at the serotonin (5-HT) 2A receptor . This review examines how DA and 5-HT modulate cortical activity and how they may interact in ways that are relevant to schizophrenia. It is concluded that although D2 receptor antagonism remains a critical factor in restoring impaired cortical activity, effects on 5-HT receptors may act in a synergistic manner on NMDA and GABA currents to potentiate antipsychotic actions in the PFC.
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7 CFR 277.18 - Establishment of an Automated Data Processing (ADP) and Information Retrieval System.
Code of Federal Regulations, 2010 CFR
2010-01-01
... activities and expenditures in relation to the approved Planning APD or Implementation APD. An APDU may also... organizations other than the State agency to perform such tasks as feasibility studies, system studies, system... requirements of § 277.18(c). Feasibility Study means a preliminary study to determine whether it is...
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ERIC Educational Resources Information Center
McKendrick, Karen; Sullivan, Christopher; Banks, Steven; Sacks, Stanley
2006-01-01
Treatment outcomes 1 year after release from prison were compared for two subgroups of male inmates with co-occurring serious mental illness and chemical abuse (MICA) disorders, those with a diagnosis for Antisocial Personality Disorder (APD), and those without a diagnosis of APD. The foundation study had randomly assigned inmates to either…
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ERIC Educational Resources Information Center
Washburn, Jason J.; Romero, Erin Gregory; Welty, Leah J.; Abram, Karen M.; Teplin, Linda A.; McClelland, Gary M.; Paskar, Leah D.
2007-01-01
Antisocial personality disorder (APD) is a serious public and mental health concern. Understanding how well conduct disorder (CD) and other mental disorders predict the development of APD among youths involved in the juvenile justice system is critical for prevention. The authors used a stratified random sample of 1,112 detained youths to examine…
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Ultraviolet Light Curves of Gaia16apd in Superluminous Supernova Models
NASA Astrophysics Data System (ADS)
Tolstov, Alexey; Zhiglo, Andrey; Nomoto, Ken'ichi; Sorokina, Elena; Kozyreva, Alexandra; Blinnikov, Sergei
2017-08-01
Observations of Gaia16apd revealed extremely luminous ultraviolet emission among superluminous supernovae (SLSNe). Using radiation hydrodynamics simulations, we perform a comparison of UV light curves, color temperatures, and photospheric velocities between the most popular SLSN models: pair-instability supernova, magnetar, and interaction with circumstellar medium. We find that the interaction model is the most promising to explain the extreme UV luminosity of Gaia16apd. The differences in late-time UV emission and in color evolution found between the models can be used to link an observed SLSN event to the most appropriate model. Observations at UV wavelengths can be used to clarify the nature of SLSNe and more attention should be paid to them in future follow-up observations.
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NASA Program Office Technology Investments to Enable Future Missions
NASA Astrophysics Data System (ADS)
Thronson, Harley; Pham, Thai; Ganel, Opher
2018-01-01
The Cosmic Origins (COR) and Physics of the Cosmos (PCOS) Program Offices (POs) reside at NASA GSFC and implement priorities for the NASA HQ Astrophysics Division (APD). One major aspect of the POs’ activities is managing our Strategic Astrophysics Technology (SAT) program to mature technologies for future strategic missions. The Programs follow APD guidance on which missions are strategic, currently informed by the NRC’s 2010 Decadal Survey report, as well as APD’s Implementation Plan and the Astrophysics Roadmap.In preparation for the upcoming 2020 Decadal Survey, the APD has established Science and Technology Definition Teams (STDTs) to study four large-mission concepts: the Origins Space Telescope (née, Far-IR Surveyor), Habitable Exoplanet Imaging Mission, Large UV/Optical/IR Surveyor, and Lynx (née, X-ray Surveyor). The STDTs will develop the science case and design reference mission, assess technology development needs, and estimate the cost of their concept. A fifth team, the L3 Study Team (L3ST), was charged to study potential US contributions to ESA’s planned Laser Interferometer Space Antenna (LISA) gravitational-wave observatory.The POs use a rigorous and transparent process to solicit technology gaps from the scientific and technical communities, and prioritize those entries based on strategic alignment, expected impact, cross-cutting applicability, and urgency. For the past two years, the technology-gap assessments of the four STDTs and the L3ST are included in our process. Until a study team submits its final report, community-proposed changes to gaps submitted or adopted by a study team are forwarded to that study team for consideration.We discuss our technology development process, with strategic prioritization informing calls for SAT proposals and informing investment decisions. We also present results of the 2017 technology gap prioritization and showcase our current portfolio of technology development projects. To date, 96 COR and 86 PCOS SAT proposals have been received, of which 22 COR and 28 PCOS projects were awarded. For more information, see the Program Annual Technology Reports available through the PO Technology web page at https://apd440.gsfc.nasa.gov/technology.html .
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Li, Ning; Csepe, Thomas A.; Hansen, Brian J.; Sul, Lidiya V.; Kalyanasundaram, Anuradha; Zakharkin, Stanislav O.; Zhao, Jichao; Guha, Avirup; Van Wagoner, David R.; Kilic, Ahmet; Mohler, Peter J; Janssen, Paul ML; Biesiadecki, Brandon; Hummel, John D; Weiss, Raul; Fedorov, Vadim V.
2016-01-01
Background Adenosine provokes atrial fibrillation (AF) with a higher activation frequency in right atria (RA) versus left atria (LA) in patients, but the underlying molecular and functional substrates are unclear. We tested the hypothesis that adenosine-induced AF is driven by localized reentry in RA areas with highest expression of adenosine A1 receptor (A1R) and its downstream GIRK channels (IK,Ado). Methods We applied bi-atrial optical mapping and immunoblot mapping of various atrial regions to reveal the mechanism of adenosine-induced AF in explanted failing and non-failing human hearts (n=37). Results Optical mapping of coronary-perfused atria (n=24) revealed that adenosine perfusion (10–100μM) produced more significant shortening of action potential durations (APD80) in RA (from 290±45ms to 239±41ms, 17.3±10.4%; p<0.01) than LA (from 307±24ms to 286±23ms, 6.7±6.6%; p<0.01). In ten hearts, adenosine induced AF (317±116 sec) that, when sustained (≥2 min), was primarily maintained by one/two localized reentrant drivers in lateral RA. Tertiapin (10–100nM), a selective GIRK channel blocker, counteracted adenosine-induced APD shortening and prevented AF induction. Immunoblotting showed that the superior/middle lateral RA had significantly higher A1R (2.7±1.7 fold; p<0.01) and GIRK4 (1.7±0.8 fold; p<0.05) protein expression than lateral/posterior LA. Conclusions This study revealed a three-fold RA-to-LA A1R protein expression gradient in the human heart, leading to significantly greater RA vs. LA repolarization sensitivity in response to adenosine. Sustained adenosine-induced AF is maintained by reentrant drivers localized in lateral RA regions with the highest A1R/GIRK4 expression. Selective atrial GIRK channel blockade may effectively treat AF during conditions with increased endogenous adenosine. PMID:27462069
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Omar, Artur; Marteinsdottir, Maria; Kadesjö, Nils; Fransson, Annette
2015-06-01
The International Commission on Radiological Protection (ICRP) has recommended that the occupational dose limit to the eye lens be substantially reduced. To ensure compliance with these recommendations, monitoring of the occupational eye lens dose is essential in certain hospital work environments. For assessment of the eye lens dose it is recommended to use a supplementary dosimeter placed at a position adjacent to the eye(s). Wearing a dosimeter at eye level can, however, be impractical and distributing and managing additional dosimeters over long periods of time is cumbersome and costly for large clinical sites. An attractive alternative is to utilize active personal dosimeters (APDs), which are routinely used by clinical staff for real-time monitoring of the personal dose equivalent rate (H(p)(10)). In this work, a formalism for the determination of eye lens dose from the response of such APD's worn on the chest is proposed and evaluated. The evaluation is based on both phantom and clinical measurements performed in an x-ray angiography suite for interventional cardiology. The main results show that the eye lens dose to the primary operator and to the assisting clinical staff can be conservatively estimated from the APD response as D(eye)(conductor) = 2.0 APD chest and D(eye)(assisting) = 1.0 APD chest, respectively. However, care should be exercised for particularly short assisting staff and if radiation protection shields are misused. These concerns can be greatly mitigated if the clinical staff are provided with adequate radiation protection training.
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Rianthavorn, Pornpimol; Limwattana, Sorawan
2015-10-01
To determine the diagnostic accuracy of anteroposterior renal pelvic diameter (APD) measurement and the society for fetal urology (SFU) grading in neonatal ultrasonography (USG) for detecting uropathy in newborns having antenatal isolated hydronephrosis (IH), characterized by hydronephrosis without ureter and bladder abnormalities, and to study time to resolution and factors predicting resolution of insignificant hydronephrosis. Ninety-six healthy newborns (129 kidneys) with IH, who underwent USG at age 7-30 days and voiding cystourethrography (VCUG) in conjunction with diuretic renography (DR) if APD > 10 mm or SFU grade 3-4 in neonatal USG, and at least a 12-month follow-up were divided into significant and insignificant hydronephrosis using the combined data of sequential USG, VCUG, and DR as the reference standard. Areas under the receiver operating characteristic plots (95 % CI) were 0.86 (0.79-0.94) versus 0.81 (0.73-0.89); p = 0.08, and 87.6 versus 79.8 % of cases were correctly classified, for APD ≥ 16 mm versus SFU grade 4, respectively. Ureteropelvic junction obstruction (UPJO) was the most common uropathy diagnosed. Of 85 kidneys with insignificant hydronephrosis, 57 underwent spontaneous resolution. The resolution rates were 24, 40, and 68 % at age 6, 12, and 24 months, respectively. APD was the only independent factor predicting resolution with the hazard ratio of 0.83 (95 % CI 0.74-0.92; p = 0.001). In IH, neonatal USG was a useful diagnostic tool to detect uropathy, mainly UPJO. Further investigation should be recommended when APD ≥ 16 mm or SFU grade 4.
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Silicone-containing aqueous polymer dispersions with hybrid particle structure.
Kozakiewicz, Janusz; Ofat, Izabela; Trzaskowska, Joanna
2015-09-01
In this paper the synthesis, characterization and application of silicone-containing aqueous polymer dispersions (APD) with hybrid particle structure are reviewed based on available literature data. Advantages of synthesis of dispersions with hybrid particle structure over blending of individual dispersions are pointed out. Three main processes leading to silicone-containing hybrid APD are identified and described in detail: (1) emulsion polymerization of organic unsaturated monomers in aqueous dispersions of silicone polymers or copolymers, (2) emulsion copolymerization of unsaturated organic monomers with alkoxysilanes or polysiloxanes with unsaturated functionality and (3) emulsion polymerization of alkoxysilanes (in particular with unsaturated functionality) and/or cyclic siloxanes in organic polymer dispersions. The effect of various factors on the properties of such hybrid APD and films as well as on hybrid particles composition and morphology is presented. It is shown that core-shell morphology where silicones constitute either the core or the shell is predominant in hybrid particles. Main applications of silicone-containing hybrid APD and related hybrid particles are reviewed including (1) coatings which show specific surface properties such as enhanced water repellency or antisoiling or antigraffiti properties due to migration of silicone to the surface, and (2) impact modifiers for thermoplastics and thermosets. Other processes in which silicone-containing particles with hybrid structure can be obtained (miniemulsion polymerization, polymerization in non-aqueous media, hybridization of organic polymer and polysiloxane, emulsion polymerization of silicone monomers in silicone polymer dispersions and physical methods) are also discussed. Prospects for further developments in the area of silicone-containing hybrid APD and related hybrid particles are presented. Copyright © 2015. Published by Elsevier B.V.
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Govender, Samantha; Khan, Nasim
2016-01-01
Audiologists managing children with auditory processing disorders (APD) encounter challenges that include conflicting definitions, several classification profiles, problems with differential diagnosis and a lack of standardised guidelines. The heterogeneity of the disorder and its concomitant childhood disorders makes diagnosis difficult. Linguistic and cultural issues are additional challenges faced by South African audiologists. The study aimed to describe the practices, challenges and recommendations of South African audiologists managing children with APD. A quantitative, non-experimental descriptive survey was used to obtain data from 156 audiologists registered with the Health Professions of South Africa. Findings revealed that 67% screened for APD, 42% assessed while 43% provided intervention. A variety of screening and assessment procedures were being administered, with no standard test battery identified. A range of intervention strategies being used are discussed. When the relationship between the number of years of experience and the audiologists’ level of preparedness to practice in the field of APD was compared, a statistically significant difference (p = 0.049) was seen in that participants with more than 10 years of experience were more prepared to practice in this area. Those participants having qualified as speech-language therapists and audiologists were significantly more prepared (p = 0.03) to practice than the audiologists who comprised the sample. Challenges experienced by the participants included the lack of linguistically and culturally appropriate screening and assessment tools and limited normative data. Recommendations included reviewing the undergraduate audiology training programmes, reinstituting the South African APD Taskforce, developing linguistically and culturally appropriate normative data, creating awareness among educators and involving them in the multidisciplinary team. PMID:27380913
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Bellis, Teri James; Ross, Jody
2011-09-01
It has been suggested that, in order to validate a diagnosis of (C)APD (central auditory processing disorder), testing using direct cross-modal analogs should be performed to demonstrate that deficits exist solely or primarily in the auditory modality (McFarland and Cacace, 1995; Cacace and McFarland, 2005). This modality-specific viewpoint is controversial and not universally accepted (American Speech-Language-Hearing Association [ASHA], 2005; Musiek et al, 2005). Further, no such analogs have been developed to date, and neither the feasibility of such testing in normally functioning individuals nor the concurrent validity of cross-modal analogs has been established. The purpose of this study was to investigate the feasibility of cross-modal testing by examining the performance of normal adults and children on four tests of central auditory function and their corresponding visual analogs. In addition, this study investigated the degree to which concurrent validity of auditory and visual versions of these tests could be demonstrated. An experimental repeated measures design was employed. Participants consisted of two groups (adults, n=10; children, n=10) with normal and symmetrical hearing sensitivity, normal or corrected-to-normal visual acuity, and no family or personal history of auditory/otologic, language, learning, neurologic, or related disorders. Visual analogs of four tests in common clinical use for the diagnosis of (C)APD were developed (Dichotic Digits [Musiek, 1983]; Frequency Patterns [Pinheiro and Ptacek, 1971]; Duration Patterns [Pinheiro and Musiek, 1985]; and the Random Gap Detection Test [RGDT; Keith, 2000]). Participants underwent two 1 hr test sessions separated by at least 1 wk. Order of sessions (auditory, visual) and tests within each session were counterbalanced across participants. ANOVAs (analyses of variance) were used to examine effects of group, modality, and laterality (for the Dichotic/Dichoptic Digits tests) or response condition (for the auditory and visual Frequency Patterns and Duration Patterns tests). Pearson product-moment correlations were used to investigate relationships between auditory and visual performance. Adults performed significantly better than children on the Dichotic/Dichoptic Digits tests. Results also revealed a significant effect of modality, with auditory better than visual, and a significant modality×laterality interaction, with a right-ear advantage seen for the auditory task and a left-visual-field advantage seen for the visual task. For the Frequency Patterns test and its visual analog, results revealed a significant modality×response condition interaction, with humming better than labeling for the auditory version but the reversed effect for the visual version. For Duration Patterns testing, visual performance was significantly poorer than auditory performance. Due to poor test-retest reliability and ceiling effects for the auditory and visual gap-detection tasks, analyses could not be performed. No cross-modal correlations were observed for any test. Results demonstrated that cross-modal testing is at least feasible using easily accessible computer hardware and software. The lack of any cross-modal correlations suggests independent processing mechanisms for auditory and visual versions of each task. Examination of performance in individuals with central auditory and pan-sensory disorders is needed to determine the utility of cross-modal analogs in the differential diagnosis of (C)APD. American Academy of Audiology.
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ERIC Educational Resources Information Center
Iliadou, Vasiliki; Bamiou, Doris Eva
2012-01-01
Purpose: To investigate the clinical utility of the Children's Auditory Processing Performance Scale (CHAPPS; Smoski, Brunt, & Tannahill, 1992) to evaluate listening ability in 12-year-old children referred for auditory processing assessment. Method: This was a prospective case control study of 97 children (age range = 11;4 [years;months] to…
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ERIC Educational Resources Information Center
Neville, Kathleen; Foley, Marie; Gertner, Alan
2011-01-01
Despite receiving increased professional and public awareness since the initial American Speech Language Hearing Association (ASHA) statement defining Auditory Processing Disorders (APDs) in 1993 and the subsequent ASHA statement (2005), many misconceptions remain regarding APDs in school-age children among health and academic professionals. While…
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Reliability of self-reported antisocial personality disorder symptoms among substance abusers.
Cottler, L B; Compton, W M; Ridenour, T A; Ben Abdallah, A; Gallagher, T
1998-02-01
It is estimated that from 20 to 60% of substance abusers meet criteria for Antisocial Personality Disorder (APD). An accurate and reliable diagnosis is important because persons meeting criteria for APD, by the nature of their disorder, are less likely to change behaviors and more likely to relapse to both substance abuse and high risk behaviors. To understand more about the reliability of the disorder and symptoms of APD, the Diagnostic Interview Schedule Version III-R (DIS) was administered to 453 substance abusers ascertained from treatment programs and from the general population (St Louis Epidemiological Catchment Area (ECA) follow-up study). Estimates of the 1 week, test-retest reliability for the childhood conduct disorder criterion, the adult antisocial behavior criterion, and APD diagnosis fell in the good agreement range, as measured by kappa. The internal consistency of these DIS symptoms was adequate to acceptable. Individual DIS criteria designed to measure childhood conduct disorder ranged from fair to good for most items; reliability was slightly higher for the adult antisocial behavior symptom items. Finally, self-reported 'liars' were no more unreliable in their reports of their behaviors than 'non-liars'.
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Short-Wave Infrared HgCdTe Electron Avalanche Photodiodes for Gated Viewing
NASA Astrophysics Data System (ADS)
Sieck, A.; Benecke, M.; Eich, D.; Oelmaier, R.; Wendler, J.; Figgemeier, H.
2018-06-01
Short-wave infrared (SWIR) HgCdTe electron avalanche photodiodes (eAPDs) with different doping profiles have been characterized for use in SWIR gated viewing systems. Gated viewing offers enhanced image contrast in scenes with clutter from the foreground or background. HgCdTe-based eAPDs show exponential gain-voltage characteristics and low excess noise and are, therefore, well suited for active imaging applications. The gain achievable at a fixed reverse voltage varies with the bandgap of the Hg1-xCdxTe detector material. We analyze current-voltage and gain-voltage plots measured on SWIR Hg1-xCdxTe eAPDs with x = 0.45, corresponding to a cutoff wavelength of 2.55 μm at 150 K. The cutoff has been chosen as a trade-off between achievable APD gain and operating temperature for SWIR gated-viewing systems with target distances of about 1000 m. Focal plane arrays with a readout-integrated circuit featuring a fast internal clock have been built and their performance with respect to gated viewing applications has been evaluated on a laboratory demonstrator for short distances. Future plans for a field demonstrator for distances up to 1000 m are described briefly at the end.
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NASA Astrophysics Data System (ADS)
Aldouri, Muthana; Aljunid, S. A.; Ahmad, R. Badlishah; Fadhil, Hilal A.
2011-06-01
In order to comprise between PIN photo detector and avalanche photodiodes in a system used double weight (DW) code to be a performance of the optical spectrum CDMA in FTTH network with point-to-multi-point (P2MP) application. The performance of PIN against APD is compared through simulation by using opt system software version 7. In this paper we used two networks designed as follows one used PIN photo detector and the second using APD photo diode, both two system using with and without erbium doped fiber amplifier (EDFA). It is found that APD photo diode in this system is better than PIN photo detector for all simulation results. The conversion used a Mach-Zehnder interferometer (MZI) wavelength converter. Also we are study, the proposing a detection scheme known as AND subtraction detection technique implemented with fiber Bragg Grating (FBG) act as encoder and decoder. This FBG is used to encode and decode the spectral amplitude coding namely double weight (DW) code in Optical Code Division Multiple Access (OCDMA). The performances are characterized through bit error rate (BER) and bit rate (BR) also the received power at various bit rate.
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A near-Infrared SETI Experiment: Alignment and Astrometric precision
NASA Astrophysics Data System (ADS)
Duenas, Andres; Maire, Jerome; Wright, Shelley; Drake, Frank D.; Marcy, Geoffrey W.; Siemion, Andrew; Stone, Remington P. S.; Tallis, Melisa; Treffers, Richard R.; Werthimer, Dan
2016-06-01
Beginning in March 2015, a Near-InfraRed Optical SETI (NIROSETI) instrument aiming to search for fast nanosecond laser pulses, has been commissioned on the Nickel 1m-telescope at Lick Observatory. The NIROSETI instrument makes use of an optical guide camera, SONY ICX694 CCD from PointGrey, to align our selected sources into two 200µm near-infrared Avalanche Photo Diodes (APD) with a field-of-view of 2.5"x2.5" each. These APD detectors operate at very fast bandwidths and are able to detect pulse widths extending down into the nanosecond range. Aligning sources onto these relatively small detectors requires characterizing the guide camera plate scale, static optical distortion solution, and relative orientation with respect to the APD detectors. We determined the guide camera plate scale as 55.9+- 2.7 milli-arcseconds/pixel and magnitude limit of 18.15mag (+1.07/-0.58) in V-band. We will present the full distortion solution of the guide camera, orientation, and our alignment method between the camera and the two APDs, and will discuss target selection within the NIROSETI observational campaign, including coordination with Breakthrough Listen.
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[Cognitive and emotional impairments in patients with protracted anxiety-phobic disorders].
Chutko, L S; Surushkina, S Iu; Iakovenko, E A; Nikishena, I S; Anisimova, T I; Bondarchuk, Iu L
2014-01-01
To study cognitive and emotional impairments in patients with anxiety-phobic disorders (APDs), to comparatively analyze the clinical manifestations of acute (less than one-year) and protracted (1-to-5-year) forms of this disease, and to evaluate the efficacy of noofen used to treat this pathology. Sixty-two patients aged 18 to 50 years with APDs were examined. The investigators collected clinical history data, performed neurological examination, and assessed autonomic disorders in accordance with the questionnaire to reveal their signs, anxiety using the Hamilton anxiety rating scale, memory impairment employing the methods developed by A.R. Luria, attention disorders applying the test of variables of attention, and diagnosed emotional intelligence using the Mayer-Salovey-Caruso emotional intelligence test. Noofen 1000 mg/day was used to treat the patients. Protracted APDs were shown to be characterized by the higher degree of psychosomatic symptoms and by more pronounced impairments in attention, memory, and emotional intelligence. The data of posttreatment clinical and psychological studiesare indicative of improvements in 73.3% of cases. The findings may lead to the conclusion that noofen is highly effective in the treatment of patients with protracted APDs.
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An excess noise measurement system for weak responsivity avalanche photodiodes
NASA Astrophysics Data System (ADS)
Qiao, Liang; Dimler, Simon J.; Baharuddin, Aina N. A. P.; Green, James E.; David, John P. R.
2018-06-01
A system for measuring, with reduced photocurrent, the excess noise associated with the gain in avalanche photodiodes (APDs), using a transimpedance amplifier front-end and based on phase-sensitive detection is described. The system can reliably measure the excess noise power of devices, even when the un-multiplied photocurrent is low (~10 nA). This is more than one order of magnitude better than previously reported systems and represents a significantly better noise signal to noise ratio. This improvement in performance has been achieved by increasing the value of the feedback resistor and reducing the op-amp bandwidth. The ability to characterise APD performance with such low photocurrents enables the use of low power light sources such as light emitting diode rather than lasers to investigate the APD noise performance.
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Ultraviolet Light Curves of Gaia16apd in Superluminous Supernova Models
DOE Office of Scientific and Technical Information (OSTI.GOV)
Tolstov, Alexey; Zhiglo, Andrey; Nomoto, Ken’ichi
2017-08-10
Observations of Gaia16apd revealed extremely luminous ultraviolet emission among superluminous supernovae (SLSNe). Using radiation hydrodynamics simulations, we perform a comparison of UV light curves, color temperatures, and photospheric velocities between the most popular SLSN models: pair-instability supernova, magnetar, and interaction with circumstellar medium. We find that the interaction model is the most promising to explain the extreme UV luminosity of Gaia16apd. The differences in late-time UV emission and in color evolution found between the models can be used to link an observed SLSN event to the most appropriate model. Observations at UV wavelengths can be used to clarify the naturemore » of SLSNe and more attention should be paid to them in future follow-up observations.« less
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Carter, Shawn A; Wu, Kevin D
2010-03-01
This study's primary goal was to examine relations between symptoms of specific social phobia (SSP), generalized social phobia (GSP), avoidant personality disorder (APD), and panic and depression. Past research has suggested a single social phobia continuum in which SSP displays less symptom severity than GSP or APD. We found SSP symptoms correlated less strongly with depression but more strongly with panic relative to both GSP and APD symptoms. These findings challenge a unidimensional model of social phobia, suggesting a multidimensional model may be more appropriate. These findings also inform current research aimed at classifying mood and anxiety disorders more broadly by identifying that the different factors of fear versus distress appear to underlie different subtypes of social phobia. 2008. Published by Elsevier Ltd.
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NASA Astrophysics Data System (ADS)
Koehler-Sidki, A.; Dynes, J. F.; Lucamarini, M.; Roberts, G. L.; Sharpe, A. W.; Yuan, Z. L.; Shields, A. J.
2018-04-01
Fast-gated avalanche photodiodes (APDs) are the most commonly used single photon detectors for high-bit-rate quantum key distribution (QKD). Their robustness against external attacks is crucial to the overall security of a QKD system, or even an entire QKD network. We investigate the behavior of a gigahertz-gated, self-differencing (In,Ga)As APD under strong illumination, a tactic Eve often uses to bring detectors under her control. Our experiment and modeling reveal that the negative feedback by the photocurrent safeguards the detector from being blinded through reducing its avalanche probability and/or strengthening the capacitive response. Based on this finding, we propose a set of best-practice criteria for designing and operating fast-gated APD detectors to ensure their practical security in QKD.
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SiC Deep Ultraviolet Avalanche Photodetectors
2010-10-01
L. Beck 1.00 Xiaogang Bai 1.00 4.00FTE Equivalent: 4Total Number: Names of Faculty Supported National Academy MemberPERCENT_SUPPORTEDNAME Joe...robust APDs capable of high gain or Geiger mode operation. Since the release of BAA 06-14, the applications originally discussed were de-emphasized...the applications identified in the original DUVAP BAA , or those for general DoD or industrial use. While GE will continue to evaluate potential
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Moore, David R; Sieswerda, Stephanie L; Grainger, Maureen M; Bowling, Alexandra; Smith, Nicholette; Perdew, Audrey; Eichert, Susan; Alston, Sandra; Hilbert, Lisa W; Summers, Lynn; Lin, Li; Hunter, Lisa L
2018-05-01
Children referred to audiology services with otherwise unexplained academic, listening, attention, language, or other difficulties are often found to be audiometrically normal. Some of these children receive further evaluation for auditory processing disorder (APD), a controversial construct that assumes neural processing problems within the central auditory nervous system. This study focuses on the evaluation of APD and how it relates to diagnosis in one large pediatric audiology facility. To analyze electronic records of children receiving a central auditory processing evaluation (CAPE) at Cincinnati Children's Hospital, with a broad goal of understanding current practice in APD diagnosis and the test information which impacts that practice. A descriptive, cross-sectional analysis of APD test outcomes in relation to final audiologist diagnosis for 1,113 children aged 5-19 yr receiving a CAPE between 2009 and 2014. Children had a generally high level of performance on the tests used, resulting in marked ceiling effects on about half the tests. Audiologists developed the diagnostic category "Weakness" because of the large number of referred children who clearly had problems, but who did not fulfill the AAA/ASHA criteria for diagnosis of a "Disorder." A "right-ear advantage" was found in all tests for which each ear was tested, irrespective of whether the tests were delivered monaurally or dichotically. However, neither the side nor size of the ear advantage predicted the ultimate diagnosis well. Cooccurrence of CAPE with other learning problems was nearly universal, but neither the number nor the pattern of cooccurring problems was a predictor of APD diagnosis. The diagnostic patterns of individual audiologists were quite consistent. The number of annual assessments decreased dramatically during the study period. A simple diagnosis of APD based on current guidelines is neither realistic, given the current tests used, nor appropriate, as judged by the audiologists providing the service. Methods used to test for APD must recognize that any form of hearing assessment probes both sensory and cognitive processing. Testing must embrace modern methods, including digital test delivery, adaptive testing, referral to normative data, appropriate testing for young children, validated screening questionnaires, and relevant objective (physiological) methods, as appropriate. Audiologists need to collaborate with other specialists to understand more fully the behaviors displayed by children presenting with listening difficulties. To achieve progress, it is essential for clinicians and researchers to work together. As new understanding and methods become available, it will be necessary to sort out together what works and what doesn't work in the clinic, both from a theoretical and a practical perspective. American Academy of Audiology.
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Compact and high-sensitivity 100-Gb/s (4 × 25 Gb/s) APD-ROSA with a LAN-WDM PLC demultiplexer.
Yoshimatsu, Toshihide; Nada, Masahiro; Oguma, Manabu; Yokoyama, Haruki; Ohno, Tetsuichiro; Doi, Yoshiyuki; Ogawa, Ikuo; Takahashi, Hiroshi; Yoshida, Eiji
2012-12-10
We demonstrate an integrated 100 GbE receiver optical sub-assembly (ROSA) that incorporates a monolithic four-channel avalanche photodiode (APD) array and a planer lightwave circuit (PLC) based LAN-WDM demultiplexer. A record minimum receiver sensitivity of -20 dBm and 50-km error-free SMF transmission without an optical amplifier have been achieved.
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Phelps, Thomas I.; Bondi, Corina O.; Mattiola, Vincent V.; Kline, Anthony E.
2016-01-01
Background Antipsychotic drugs (APDs) are used to manage traumatic brain injury (TBI)-induced behavioral disturbances, such as agitation and aggression. However, APDs exhibiting D2 receptor antagonism impede cognitive recovery after experimental TBI. Hence, empirical evaluation of APDs with different mechanistic actions is warranted. Aripiprazole (ARIP) is a D2 and 5-HT1A receptor agonist; pharmacotherapies with these properties enhance cognition after TBI. Objective To test the hypothesis that ARIP would increase behavioral performance and decrease histopathology after TBI. Methods Adult male rats were subjected to either a controlled cortical impact (CCI) or sham injury and then randomly assigned to ARIP (0.1 or 1.0 mg/kg) or VEH (1.0 mL/kg, saline vehicle) groups. Treatments began 24 hr after surgery and were administered once daily for 19 days. Motor (beam-balance/beam-walk) and cognitive (Morris water maze) performance was assessed on post-operative days 1-5 and 14-19, respectively, followed by quantification of hippocampal CA1/3 neuron survival and cortical lesion volume. Results Beam-balance was significantly improved in the CCI + ARIP (1.0 mg/kg) group vs. CCI + ARIP (0.1 mg/kg) and CCI + VEH [p<0.05]. Spatial learning and memory retention were significantly improved in the CCI + ARIP (0.1 mg/kg) group vs. the CCI + ARIP (1.0 mg/kg) and CCI + VEH groups [p<0.05]. Both doses of ARIP reduced lesion size and CA3 cell loss vs. VEH [p<0.05]. Importantly, neither dose of ARIP impeded functional recovery as previously reported with other APDs. Conclusion These findings support the hypothesis and endorse ARIP as a safer APD for alleviating behavioral disturbances after TBI. PMID:27225976
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Barak, Segev; Weiner, Ina
2011-08-01
Several developments have converged to drive what may be called "the cognitive revolution" in drug discovery in schizophrenia (SCZ), including the emphasis on cognitive deficits as a core disabling aspect of SCZ, the increasing consensus that cognitive deficits are not treated satisfactorily by the available antipsychotic drugs (APDs), and the failure of animal models to predict drug efficacy for cognitive deficits in clinical trials. Consequently, in recent years, a paradigm shift has been encouraged in animal modeling, triggered by the NIMH sponsored Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, and intended to promote the development and use of behavioral measures in animals that can generate valid (clinically relevant) measures of cognition and thus promote the identification of cognition enhancers for SCZ. Here, we provide a non-exhaustive survey of the effects of putative cognition enhancers (PCEs) representing 10 pharmacological targets as well as antipsychotic drugs (APDs), on SCZ-mimetic drugs (NMDA antagonists, muscarinic antagonist scopolamine and dopaminergic agonist amphetamine), in several tasks considered to measure cognitive processes/domains that are disrupted in SCZ (the five choice serial reaction time task, sustain attention task, working and/or recognition memory (delayed (non)matching to sample, delayed alternation task, radial arm maze, novel object recognition), reversal learning, attentional set shifting, latent inhibition and spatial learning and memory). We conclude that most of the available models have no capacity to distinguish between PCEs and APDs and that there is a need to establish models based on tasks whose perturbations lead to performance impairments that are resistant to APDs, and/or to accept APDs as a "weak gold standard". Several directions derived from the surveyed data are suggested. Copyright © 2011 Elsevier Inc. All rights reserved.
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Design and performance of single photon APD focal plane arrays for 3-D LADAR imaging
NASA Astrophysics Data System (ADS)
Itzler, Mark A.; Entwistle, Mark; Owens, Mark; Patel, Ketan; Jiang, Xudong; Slomkowski, Krystyna; Rangwala, Sabbir; Zalud, Peter F.; Senko, Tom; Tower, John; Ferraro, Joseph
2010-08-01
×We describe the design, fabrication, and performance of focal plane arrays (FPAs) for use in 3-D LADAR imaging applications requiring single photon sensitivity. These 32 × 32 FPAs provide high-efficiency single photon sensitivity for three-dimensional LADAR imaging applications at 1064 nm. Our GmAPD arrays are designed using a planarpassivated avalanche photodiode device platform with buried p-n junctions that has demonstrated excellent performance uniformity, operational stability, and long-term reliability. The core of the FPA is a chip stack formed by hybridizing the GmAPD photodiode array to a custom CMOS read-out integrated circuit (ROIC) and attaching a precision-aligned GaP microlens array (MLA) to the back-illuminated detector array. Each ROIC pixel includes an active quenching circuit governing Geiger-mode operation of the corresponding avalanche photodiode pixel as well as a pseudo-random counter to capture per-pixel time-of-flight timestamps in each frame. The FPA has been designed to operate at frame rates as high as 186 kHz for 2 μs range gates. Effective single photon detection efficiencies as high as 40% (including all optical transmission and MLA losses) are achieved for dark count rates below 20 kHz. For these planar-geometry diffused-junction GmAPDs, isolation trenches are used to reduce crosstalk due to hot carrier luminescence effects during avalanche events, and we present details of the crosstalk performance for different operating conditions. Direct measurement of temporal probability distribution functions due to cumulative timing uncertainties of the GmAPDs and ROIC circuitry has demonstrated a FWHM timing jitter as low as 265 ps (standard deviation is ~100 ps).
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HgCdTe APDs for time-resolved space applications
NASA Astrophysics Data System (ADS)
Rothman, J.; Lasfargues, G.; Delacourt, B.; Dumas, A.; Gibert, F.; Bardoux, A.; Boutillier, M.
2017-12-01
The use of HgCdTe avalanche photodiodes (APDs) for resolving the temporal variation of faint light level signals is analyzed. The analysis is based on the performance characteristics such as the gain, the response time, and dark currents in the APDs, measured as a function of operating temperature and Cd composition, and on recently developed detector demonstrator modules. The choice of Cd composition in the APDs is strongly dependent on the application needs in terms of electrical bandwidth and signal-to-noise ratio. A performance model has been developed and used to predict the performance of the future detector modules for different applications such as high bandwidth and/or deep space free space optical telecommunications and lidar, associated with sensitivities down to single photon level at low operating temperature and close to single-photon operation at bandwidth of 10 GHz at room temperature. The predictions are corroborated by the results obtained on detector modules that have been developed and used in lidar and deep space optical communications. In a first lidar prototype, integrating a 200 µm APD, we obtained a maximum sensitivity of 25 fW/√Hz at T = 190 K operating temperature. The detector has been used for differential absorption lidar estimations of the absorption due to presence of CO2 in the atmosphere. A random error of 3-10% was obtained for the estimation of the optical thickness at a distance of 100-3000 m, for a range resolution of 100 m and using and averaging time of 4 s. The pursuit of this development is pending on the space qualification of the technology. Results from first proton and irradiation tests are reported that shows on a close to constant performance during and after the irradiation and endurance tests.
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Glucose absorption in acute peritoneal dialysis.
Podel, J; Hodelin-Wetzel, R; Saha, D C; Burns, G
2000-04-01
During acute peritoneal dialysis (APD), it is known that glucose found in the dialysate solution contributes to the provision of significant calories. It has been well documented in continuous ambulatory peritoneal dialysis (CAPD) that glucose absorption occurs. In APD, however, it remains unclear how much glucose absorption actually does occur. Therefore, the purpose of this study was to determine whether it is appropriate to use the formula used to calculate glucose absorption in CAPD (Grodstein et al) among patients undergoing APD. Actual measurements of glucose absorption (Method I) were calculated in 9 patients undergoing APD treatment for >24 hours who were admitted to the intensive care unit. Glucose absorption using the Grodstein et al formula (Method II) was also determined and compared with the results of actual measurements. The data was then further analyzed based on the factors that influence glucose absorption, specifically dwell time and concentration. The mean total amount of glucose absorbed was 43% +/- 15%. However, when dwell time and concentration were further examined, significant differences were noted. Method I showed a cumulative increase over time. Method II showed that absorption was fixed. This suggests that with the variation in dwell time commonly seen in the acute care setting, the use of Method II may not be accurate. In each of the 2 methods, a significant difference in glucose absorption was noted when comparing the use of 1.5% and 4.25% dialysate concentrations. The established formula designed for CAPD should not be used for calculating glucose absorption in patients receiving APD because variation in dwell time and concentration should be taken into account. Because of the time constraints and staffing required to calculate each exchange individually, combined with the results of the study, we recommend the use of the percentage estimate of 40% to 50%.
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Integrated three-dimensional optical MEMS for chip-based fluorescence detection
NASA Astrophysics Data System (ADS)
Hung, Kuo-Yung; Tseng, Fan-Gang; Khoo, Hwa-Seng
2009-04-01
This paper presents a novel fluorescence sensing chip for parallel protein microarray detection in the context of a 3-in-1 protein chip system. This portable microchip consists of a monolithic integration of CMOS-based avalanche photo diodes (APDs) combined with a polymer micro-lens, a set of three-dimensional (3D) inclined mirrors for separating adjacent light signals and a low-noise transformer-free dc-dc boost mini-circuit to power the APDs (ripple below 1.28 mV, 0-5 V input, 142 V and 12 mA output). We fabricated our APDs using the planar CMOS process so as to facilitate the post-CMOS integration of optical MEMS components such as the lenses. The APD arrays were arranged in unique circular patterns appropriate for detecting the specific fluorescently labelled protein spots in our study. The array-type APDs were designed so as to compensate for any alignment error as detected by a positional error signal algorithm. The condenser lens was used as a structure for light collection to enhance the fluorescent signals by about 25%. This element also helped to reduce the light loss due to surface absorption. We fabricated an inclined mirror to separate two adjacent fluorescent signals from different specimens. Excitation using evanescent waves helped reduce the interference of the excitation light source. This approach also reduced the number of required optical lenses and minimized the complexity of the structural design. We achieved detection floors for anti-rabbit IgG and Cy5 fluorescent dye as low as 0.5 ng/µl (~3.268 nM). We argue that the intrinsic nature of point-to-point and batch-detection methods as showcased in our chip offers advantages over the serial-scanning approach used in traditional scanner systems. In addition, our system is low cost and lightweight.
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Time Course of Peritoneal Function in Automated and Continuous Peritoneal Dialysis
Michels, Wieneke M.; Verduijn, Marion; Parikova, Alena; Boeschoten, Elisabeth W.; Struijk, Dirk G.; Dekker, Friedo W.; Krediet, Raymond T.
2012-01-01
♦ Background and Objectives: In automated peritoneal dialysis (APD), a patient’s peritoneal membrane is more intensively exposed to fresh dialysate than it is in continuous ambulatory peritoneal dialysis (CAPD). Our aim was to study, in incident peritoneal dialysis (PD) patients, the influence of APD—compared with that of CAPD—on peritoneal transport over 4 years. ♦ Design, Setting, Participants, and Measurements: Patients were included if at least 2 annual standard permeability analyses (SPAs) performed with 3.86% glucose were available while the patient was using the same modality with which they had started PD (APD or CAPD). Patients were followed until their first modality switch. Differences in the pattern of SPA outcomes over time were tested using repeated-measures models adjusted for age, sex, comorbidity, primary kidney disease, and year of PD start. ♦ Results: The 59 CAPD patients enrolled were older than the 47 APD patients enrolled (mean age: 58 ± 14 years vs 49 ± 14 years; p < 0.01), and they had started PD earlier (mean start year: 2000 vs 2002). Over time, no differences in solute (p > 0.19) or fluid transport (p > 0.13) were observed. Similarly, free water transport (p = 0.43) and small-pore transport (p = 0.31) were not different between the modalities. Over time, patients on APD showed a faster decline in effective lymphatic absorption rate (ELAR: p = 0.02) and in transcapillary ultrafiltration (TCUF: p = 0.07, adjusted p = 0.05). Further adjustment did not change the results. ♦ Conclusions: Compared with patients starting on CAPD, those starting on APD experienced a faster decline in ELAR and TCUF. Other transport parameters were not different over time between the groups. PMID:22473037
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Deng, Shijie; Morrison, Alan P
2012-09-15
This Letter presents an active quench-and-reset circuit for Geiger-mode avalanche photodiodes (GM-APDs). The integrated circuit was fabricated using a conventional 0.35 μm complementary metal oxide semiconductor process. Experimental results show that the circuit is capable of linearly setting the hold-off time from several nanoseconds to microseconds with a resolution of 6.5 ns. This allows the selection of the optimal afterpulse-free hold-off time for the GM-APD via external digital inputs or additional signal processing circuitry. Moreover, this circuit resets the APD automatically following the end of the hold-off period, thus simplifying the control for the end user. Results also show that a minimum dead time of 28.4 ns is achieved, demonstrating a saturated photon-counting rate of 35.2 Mcounts/s.
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HgCdTe APDS for time resolved space applications
NASA Astrophysics Data System (ADS)
Rothman, J.; Lasfargues, G.; Delacourt, B.; Dumas, A.; Gibert, F.; Bardoux, A.; Boutillier, M.
2017-09-01
HgCdTe APDs have opened a new horizon in photon starved applications due to their exceptional performance in terms of high linear gain, low excess noise and high quantum efficiency. Both focal plane arrays (FPAs) and large array single element using HgCdTe (MCT) APDs have been developed at CEA/Leti and Sofradir and high performance devices are at present available to detect without deterioration the spatial and/or temporal information in photon fluxes with a low number of photon in each spatio-temporal bin. The enhancement in performance that can be achieved with MCT has subsequently been demonstrated in a wide scope of applications such as astronomical observations, active imaging, deep space telecommunications, atmospheric LIDAR and mid-IR (MIR) time resolved photoluminescence measurements. Most of these applications can be used in space borne platforms.
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Harsh-Environment Solid-State Gamma Detector for Down-hole Gas and Oil Exploration
DOE Office of Scientific and Technical Information (OSTI.GOV)
Peter Sandvik; Stanislav Soloviev; Emad Andarawis
2007-08-10
The goal of this program was to develop a revolutionary solid-state gamma-ray detector suitable for use in down-hole gas and oil exploration. This advanced detector would employ wide-bandgap semiconductor technology to extend the gamma sensor's temperature capability up to 200 C as well as extended reliability, which significantly exceeds current designs based on photomultiplier tubes. In Phase II, project tasks were focused on optimization of the final APD design, growing and characterizing the full scintillator crystals of the selected composition, arranging the APD device packaging, developing the needed optical coupling between scintillator and APD, and characterizing the combined elements asmore » a full detector system preparing for commercialization. What follows is a summary report from the second 18-month phase of this program.« less
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Optical Communications With A Geiger Mode APD Array
2016-02-09
spurious fires from numerous sources, including crosstalk from other detectors in the same array . Additionally, after a 9 successful detection, the...be combined into arrays with large numbers of detectors , allowing for scaling of dynamic range with relatively little overhead on space and power...overall higher rate of dark counts than a single detector , this is more than compensated for by the extra detectors . A sufficiently large APD array could
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Single photon counting linear mode avalanche photodiode technologies
NASA Astrophysics Data System (ADS)
Williams, George M.; Huntington, Andrew S.
2011-10-01
The false count rate of a single-photon-sensitive photoreceiver consisting of a high-gain, low-excess-noise linear-mode InGaAs avalanche photodiode (APD) and a high-bandwidth transimpedance amplifier (TIA) is fit to a statistical model. The peak height distribution of the APD's multiplied dark current is approximated by the weighted sum of McIntyre distributions, each characterizing dark current generated at a different location within the APD's junction. The peak height distribution approximated in this way is convolved with a Gaussian distribution representing the input-referred noise of the TIA to generate the statistical distribution of the uncorrelated sum. The cumulative distribution function (CDF) representing count probability as a function of detection threshold is computed, and the CDF model fit to empirical false count data. It is found that only k=0 McIntyre distributions fit the empirically measured CDF at high detection threshold, and that false count rate drops faster than photon count rate as detection threshold is raised. Once fit to empirical false count data, the model predicts the improvement of the false count rate to be expected from reductions in TIA noise and APD dark current. Improvement by at least three orders of magnitude is thought feasible with further manufacturing development and a capacitive-feedback TIA (CTIA).
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Henry, Brandon; Clark, Philip; Sudan, Ranjan
2014-02-01
The cost and logistics of deploying the American College of Surgeons (ACS)/Association of Program Directors in Surgery (APDS) National Technical Skills Curriculum across all training years are not known. This information is essential for residency programs choosing to adopt similar curricula. A task force evaluated the authors' institution's existing simulation curriculum and enhanced it by implementing the ACS/APDS modules. A 35-module curriculum was administered to 35 general surgery residents across all 5 clinical years. The costs and logistics were noted, and resident satisfaction was assessed. The annual operational cost was $110,300 ($3,150 per resident). Cost per module, per resident was $940 for the cadaveric module compared with $220 and $240 for dry simulation and animal tissue-based modules, respectively. Resident satisfaction improved from 2.45 to 4.78 on a 5-point, Likert-type scale after implementing the ACS/APDS modules. The ACS/APDS skills curriculum was implemented successfully across all clinical years. Cadaveric modules were the most expensive. Animal and dry simulation modules were equivalent in cost. The addition of tissue-based modules was associated with high satisfaction. Copyright © 2014 Elsevier Inc. All rights reserved.
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Okano, Tsubasa; Imai, Kohsuke; Tsujita, Yuki; Mitsuiki, Noriko; Yoshida, Kenichi; Kamae, Chikako; Honma, Kenichi; Mitsui-Sekinaka, Kanako; Sekinaka, Yujin; Kato, Tamaki; Hanabusa, Katsuyuki; Endo, Eri; Takashima, Takehiro; Hiroki, Haruka; Yeh, Tzu-Wen; Tanaka, Keisuke; Nagahori, Masakazu; Tsuge, Ikuya; Bando, Yuki; Iwasaki, Fuminori; Shikama, Yoshiaki; Inoue, Masami; Kimoto, Tomiko; Moriguchi, Naohiko; Yuza, Yuki; Kaneko, Takashi; Suzuki, Kyoko; Matsubara, Tomoyo; Maruo, Yoshihiro; Kunitsu, Tomoaki; Waragai, Tomoko; Sano, Hideki; Hashimoto, Yuko; Tasaki, Kazuhiro; Suzuki, Osamu; Shirakawa, Toshihiko; Kato, Motohiro; Uchiyama, Toru; Ishimura, Masataka; Tauchi, Tetsuzo; Yagasaki, Hiroshi; Jou, Shiann-Tarng; Yu, Hsin-Hui; Kanegane, Hirokazu; Kracker, Sven; Durandy, Anne; Kojima, Daiei; Muramatsu, Hideki; Wada, Taizo; Inoue, Yuzaburo; Takada, Hidetoshi; Kojima, Seiji; Ogawa, Seishi; Ohara, Osamu; Nonoyama, Shigeaki; Morio, Tomohiro
2018-05-17
Activated phosphatidylinositol-3-OH kinase-delta (PI3Kδ) syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory infections, lymphoid hyperplasia, and herpesviridae infections due to germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) may be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, method, and outcomes of HSCT for APDS1 remain undefined. Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. We retrospectively reviewed the medical records of cohorts undergoing HSCT at collaborating facilities. Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence, and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced intensity conditioning (RIC). Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based RIC-HSCT ameliorated clinical symptoms, but transplant-related complications were frequent, including graft failure. Copyright © 2018. Published by Elsevier Inc.
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Weidenauer, U; Bodmer, D; Kissel, T
2004-03-01
The prolonged delivery of hydrophilic drug salts from hydrophobic polymer carriers at high drug loading is an ambitious goal. Pamidronate disodium salt (APD) containing implants prepared from spray-dried microparticles were investigated using a laboratory ram extruder. An APD-containing polymer matrix consisting of an APD-chitosan implant embedded in the biodegradable polymer D,L-poly(lactide-co-glycolide acid-glucose) (PLG-GLU) was compared with a matrix system with the micronized drug distributed in the PLG-GLU. The APD-chitosan matrix system showed a triphasic release behaviour at loading levels of 6.86 and 15.54% (w/w) over 36 days under in-vitro conditions. At higher loading (31.92%), a drug burst was observed within 6 days due to the formation of pores and channels in the polymeric matrix. In contrast, implants containing the micronized drug showed a more continuous release profile over 48 days up to a loading of 31.78% (w/w). At a drug loading of 46.17% (w/w), a drug burst was observed. Using micronized drug salts and reducing the surface area available for diffusion, parenteral delivery systems for highly water-soluble drug candidates were shown to be technically feasible at high drug loadings.
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Acidogenesis and Two-Phase Codigestion of Fats, Oils, and Greases and Municipal Biosolids.
Varin, Ross; Novak, John; Bott, Charles
2016-11-01
Acidogenic codigestion of fats, oils, and greases (FOG) was studied using suspended growth sludge digesters operated as batch fed reactors that were fed twice daily. The digesters were maintained at a 2-day retention time and at 37 °C to mimic the acid phase of an acid-gas digestion system. As FOG loading rates increased, volatile fatty acid (VFA) production was found to increase, although the percentage of VFA production compared to theoretical values decreased exponentially to just 20% at the highest loading rates. FOG matter was found to have accumulated in the reactor vessel in semi-solid balls that floated near the liquid surface. Two-phase codigestion of FOG was studied at 37 °C using Continuously Stirred Tank Reactors (CSTRs) as acid phase digesters (APD) operated with 2-day retention times, followed by gas phase digesters (GPD) with 15-day retention times. The two-phase systems were compared by FOG addition to the APD versus GPD. FOG addition to the APD resulted in 88% destruction of LCFAs, whereas FOG addition to the GPD resulted in 95% destruction of LCFAs. Accumulated LCFAs were found in the APD receiving FOG and were primarily composed palmitic acid (16:0), followed by oleic acid (18:1) and stearic acid (18:0).
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Eschenbeck, Heike; Gillé, Vera; Heim-Dreger, Uwe; Schock, Alexandra; Schott, Andrea
2017-01-01
This study evaluated stressors and coping strategies in 70 children who are deaf or hard of hearing (D/HH) or with auditory processing disorder (APD) attending Grades 5 and 6 of a school for deaf and hard-of-hearing children. Everyday general stressors and more hearing-specific stressors were examined in a hearing-specific modified stress and coping questionnaire. Reports were compared with normative data for hearing children. Regarding everyday general stressors, stress levels for children who are D/HH or with APD did not differ from those of hearing children. Within children with hearing problems, everyday stressors were experienced as more stressful than hearing-specific stressors. For coping strategies, differences between children with hearing problems (D/HH, APD) and hearing children were shown (i.e., problem solving, anger-related emotion regulation). Girls scored higher in seeking social support whereas boys reported higher amounts of media use as a way of coping. Differences regarding stress and coping between children who are D/HH and children with APD were minor; D/HH children reported more social support seeking. Implications for assessment and resource promotion are discussed. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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The Danish test battery for auditory processing disorder evaluated with patient and control data.
Raben Pedersen, Ellen
2018-06-10
This study evaluates the Danish test battery for auditory processing disorder (APD). The battery consists of four behavioural tests, two speech and two non-speech stimuli tests. The evaluation includes determination of: (1) new cut-off values (pass-fail criteria), (2) the sensitivity and the specificity of the entire test battery and (3) the failure rate of different test combinations. For each test in the battery, cut-off values were determined using the weighted Youden index. Applying the newly derived cut-off values, the distribution of failing specific test combinations was determined. A group of 112 children diagnosed with APD (57 boys, 55 girls, aged 6-16 years) and a control group containing 158 children without auditory problems (75 boys, 83 girls, aged 6-16 years). Cut-off values for different weights of the sensitivity and the specificity have been determined. Using the criterion that at least two tests have to be failed for APD to be suspected, the sensitivity and the specificity of the entire test battery were 95.3% and 91.6%, respectively. Some test combinations were found to have higher failure rates than others. Due to the high sensitivity and specificity the test battery has good predictive value in APD assessment.
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NASA Astrophysics Data System (ADS)
Majumder, Rupamanjari; Engels, Marc C.; de Vries, Antoine A. F.; Panfilov, Alexander V.; Pijnappels, Daniël A.
2016-04-01
Fibrosis and altered gap junctional coupling are key features of ventricular remodelling and are associated with abnormal electrical impulse generation and propagation. Such abnormalities predispose to reentrant electrical activity in the heart. In the absence of tissue heterogeneity, high-frequency impulse generation can also induce dynamic electrical instabilities leading to reentrant arrhythmias. However, because of the complexity and stochastic nature of such arrhythmias, the combined effects of tissue heterogeneity and dynamical instabilities in these arrhythmias have not been explored in detail. Here, arrhythmogenesis was studied using in vitro and in silico monolayer models of neonatal rat ventricular tissue with 30% randomly distributed cardiac myofibroblasts and systematically lowered intercellular coupling achieved in vitro through graded knockdown of connexin43 expression. Arrhythmia incidence and complexity increased with decreasing intercellular coupling efficiency. This coincided with the onset of a specialized type of spatially discordant action potential duration alternans characterized by island-like areas of opposite alternans phase, which positively correlated with the degree of connexinx43 knockdown and arrhythmia complexity. At higher myofibroblast densities, more of these islands were formed and reentrant arrhythmias were more easily induced. This is the first study exploring the combinatorial effects of myocardial fibrosis and dynamic electrical instabilities on reentrant arrhythmia initiation and complexity.
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Islam, Mohammed A
2010-01-01
Despite the emerging new insights into our understandings of the cellular mechanisms underlying cardiac arrhythmia, medical therapy for this disease remains unsatisfactory. Atrial fibrillation (AF), the most prevalent arrhythmia, is responsible for significant morbidity and mortality. On the other hand, ventricular fibrillation results in sudden cardiac deaths in many instances. Prolongation of cardiac action potential (AP) is a proven principle of antiarrhythmic therapy. Class III antiarrhythmic agents prolong AP and QT interval by blocking rapidly activating delayed rectifier current (I(Kr)). However, I(Kr) blocking drugs carry the risk of life-threatening proarrhythmia. Recently, modulation of atrial-selective ultra-rapid delayed rectifier current (I(Kur)), has emerged as a novel therapeutic approach to treat AF. A number of I(Kur) blockers are being evaluated for the treatment of AF. The inhibition of slowly activating delayed rectifier current (I(Ks)) has also been proposed as an effective and safer antiarrhythmic approach because of its distinguishing characteristics that differ in remarkable ways from other selective class III agents. Selective I(Ks) block may prolong AP duration (APD) at rapid rates without leading to proarrhythmia. This article reviews the pathophysiological roles of I(Kur) and I(Ks) in cardiac repolarization and the implications of newly developed I(Kur) and I(Ks) blocking agents as promising antiarrhythmic approaches. Several recent patents pertinent to antiarrhythmic drug development have been discussed. Further research will be required to evaluate the efficacy and safety of these agents in the clinical setting.
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Low-temperature photoluminescence study of thin epitaxial GaAs films on Ge substrates
NASA Astrophysics Data System (ADS)
Brammertz, Guy; Mols, Yves; Degroote, Stefan; Motsnyi, Vasyl; Leys, Maarten; Borghs, Gustaaf; Caymax, Matty
2006-05-01
Thin epitaxial GaAs films, with thickness varying from 140 to 1000 nm and different Si doping levels, were grown at 650 °C by organometallic vapor phase epitaxy on Ge substrates and analyzed by low-temperature photoluminescence (PL) spectroscopy. All spectra of thin GaAs on Ge show two different structures, one narrow band-to-band (B2B) structure at an energy of ~1.5 eV and a broad inner-band-gap (IB) structure at an energy of ~1.1 eV. Small strain in the thin GaAs films causes the B2B structure to be separated into a light-hole and a heavy-hole peak. At 2.5 K the good structural quality of the thin GaAs films on Ge can be observed from the narrow excitonic peaks. Peak widths of less than 1 meV are measured. GaAs films with thickness smaller than 200 nm show B2B PL spectra with characteristics of an n-type doping level of approximately 1018 at./cm3. This is caused by heavy Ge diffusion from the substrate into the GaAs at the heterointerface between the two materials. The IB structure observed in all films consists of two Gaussian peaks with energies of 1.04 and 1.17 eV. These deep trapping states arise from Ge-based complexes formed within the GaAs at the Ge-GaAs heterointerface, due to strong diffusion of Ge atoms into the GaAs. Because of similarities with Si-based complexes, the peak at 1.04 eV was identified to be due to a GeGa-GeAs complex, whereas the peak at 1.17 eV was attributed to the GeGa-VGa complex. The intensity of the IB structure decreases strongly as the GaAs film thickness is increased. PL intensity of undoped GaAs films containing antiphase domains (APDs) is four orders of magnitude lower than for similar films without APDs. This reduction in intensity is due to the electrically active Ga-Ga and As-As bonds at the boundaries between the different APDs. When the Si doping level is increased, the PL intensity of the APD-containing films is increased again as well. A film containing APDs with a Si doping level of ~1018 at./cm3 has only a factor 10 reduced intensity. We tentatively explain this observation by Si or Ge clustering at antiphase boundaries, which eliminates the effects of the Ga-Ga and As-As bonds. This assumption is confirmed by the fact that, at 77 K, the ratio between the intensity of the IB peak at 1.17 eV to the intensity of the peak at 1.04 eV is smaller than 1.4 for all films containing APDs, whereas it is larger than 1.4 for all films without APDs. This shows stronger clustering of Si or Ge in the material with APDs. For future electronic applications, Ge diffusion into the GaAs will have to be reduced. PL analysis will be a rapid tool for studying the Ge diffusion into the GaAs thin films.
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Redding, David W.; Mooers, Arne O.; Şekercioğlu, Çağan H.; Collen, Ben
2015-01-01
Understanding how to prioritize among the most deserving imperilled species has been a focus of biodiversity science for the past three decades. Though global metrics that integrate evolutionary history and likelihood of loss have been successfully implemented, conservation is typically carried out at sub-global scales on communities of species rather than among members of complete taxonomic assemblages. Whether and how global measures map to a local scale has received little scrutiny. At a local scale, conservation-relevant assemblages of species are likely to be made up of relatively few species spread across a large phylogenetic tree, and as a consequence there are potentially relatively large amounts of evolutionary history at stake. We ask to what extent global metrics of evolutionary history are useful for conservation priority setting at the community level by evaluating the extent to which three global measures of evolutionary isolation (evolutionary distinctiveness (ED), average pairwise distance (APD) and the pendant edge or unique phylogenetic diversity (PD) contribution) capture community-level phylogenetic and trait diversity for a large sample of Neotropical and Nearctic bird communities. We find that prioritizing the most ED species globally safeguards more than twice the total PD of local communities on average, but that this does not translate into increased local trait diversity. By contrast, global APD is strongly related to the APD of those same species at the community level, and prioritizing these species also safeguards local PD and trait diversity. The next step for biologists is to understand the variation in the concordance of global and local level scores and what this means for conservation priorities: we need more directed research on the use of different measures of evolutionary isolation to determine which might best capture desirable aspects of biodiversity. PMID:25561674
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NASA Technical Reports Server (NTRS)
Davidson, Frederic M.; Sun, Xiaoli; Field, Christopher T.
1994-01-01
This interim report consists of two reports: 'Space Radiation Effects on Si APDs for GLAS' and 'Computer Simulation of Avalanche Photodiode and Preamplifier Output for Laser Altimeters.' The former contains a detailed description of our proton radiation test of Si APD's performed at the Brookhaven National Laboratory. The latter documents the computer program subroutines which were written for the upgrade of NASA's GLAS simulator.
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Acquired perforating dermatosis in a patient with Poland syndrome.
Fistarol, Susanna K; Itin, Peter H
2003-01-01
Acquired perforating dermatosis (APD) is characterized by umbilicated 1- to 10-mm-measuring papulonodules with a central adherent oystershell-like keratotic plug, typically on the dorsa of the hands, forearms and over the knees. APD is associated with systemic diseases, especially diabetes mellitus and/or renal failure. Histologically the lesions show transepidermal elimination of altered dermal components into a cup-shaped epidermal depression. We present a 69-year-old man with coexisting APD and Poland syndrome (PS), an association not yet described. PS (OMIM 173800) is a rare congenital anomaly consisting of unilateral partial or total absence of the greater pectoralis muscle and ipsilateral symbrachydactyly. Most cases of PS are sporadic as it was in our case. Our patient had, in addition, an untreated diabetic condition, hyperuricaemia, dilated cardiomyopathy and a very recent pulmonary embolism. He responded to therapy with allopurinol. Copyright 2003 S. Karger AG, Basel
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NASA Technical Reports Server (NTRS)
Benton, E. V.; Frank, A. L.; Benton, E. R.
1998-01-01
As part of the NASA/Mir Phase 1B Science Program, the ionizing radiation environment inside and outside the Russian Mir's Space Station was monitored using a combination of Thermoluminescent Detectors (TLD) and CR-39 Plastic Nuclear Track Detectors (PNTD). Radiation measurements inside the Mir station were carried out using six Area Passive Dosimeters (APD), four located inside the Mir Base Block and two located inside the Kvant 2 module, during the NASA-2/Mir-21, NASA-3/Mir-22 and NASA-4/Mir-23 missions. The radiation environment under low shielding was measured using an External Dosimeter Array (EDA) mounted on the outer surface of the Kvant 2 module. The external radiation environment and a location inside the Kvant 2 roughly corresponding to the location of the EDA were monitored for 130 days during the NASA- 4/Mir-23 and NASA-5/Mir-24 missions. Dose rates measured by APD TLDs ranged from 271 to 407 microGy/d during the NASA-2/Mir-21 mission, from 265 to 378 microGy/d during the NASA-3/Mir-22 mission, and from 287 to 421 microGy/d during the NASA-4/Mir-23 mission. APD PNTDs have been analyzed and LET spectra have been Cenerated for the five APDs exposed on the NASA-2/Mir-21 mission and for two APD PNTDs exposed on the NASA-3/Mir-22 mission. Dose equivalent rates on the NASA-2/Mir-21 mission ranged from 513 microSv/d in the Kvant 2 module to 710 microSv/d on the floor of the Base Block. Dose as a function of shielding depth in TLDs has been measured in the thin TLD stacks including in the EDA. EDA dose range from 72.5 Gy under 0.0146 g/sq cm to 0.093 Gy under 3.25 g/sq cm of shielding. Readout and analysis of the reaming PNTDs form the NASA-3/Mir-22 mission and PNTDs from the NASA-4/Mir-23 mission (including those from the EDA) is ongoing and will be completed during the final year of this experiment. Dose equivalent rates for the NASA-3/Mir-22 and NASA-4/Mir-23 APDs will then be determined and comparisons will be made with both model calculations and with results from similar measurements.
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Avalanche photodiode for measurement of low-energy electrons
NASA Astrophysics Data System (ADS)
Ogasawara, K.; Asamura, K.; Mukai, T.; Saito, Y.
2005-06-01
We report on the performance of an Avalanche Photodiode (APD) produced by Hamamatsu Photonics Co. Ltd. (Type Z7966-20) for measurements of low energy electrons. We have set up an electron gun, which can generate a 1-20 keV electron beam impinging onto the APD in a vacuum chamber. The result shows that the pulse height distribution (PHD) of the APD signal exhibits a significant peak for electrons with energies above 8 keV, and the variation of the PHD peak shows a good linearity with the energy of incident electrons. The energy resolution is quite good, though it slightly depends on the electron energy. In the case of low-energies (lower than 10 keV), the pulse height distribution has a characteristic tail on the low energy side, and the energy resolution becomes a little worse. The position of the peak appears on a slightly lower channel than is expected from data at higher energies (near 20 keV). Qualitatively, the low-energy tail is caused by the dead-layer on the surface of the device. The nonlinearity and the worse resolution of the peaks for higher energy electrons may have resulted from a space-charge effect due to created e-h pairs. For a quantitative understanding, we have made a Monte Carlo particle simulation of charge transport and collection inside the APD.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Xu, Fan; Wang, Yuanqing, E-mail: yqwang@nju.edu.cn; Li, Fenfang
The avalanche-photodiode-array (APD-array) laser detection and ranging (LADAR) system has been continually developed owing to its superiority of nonscanning, large field of view, high sensitivity, and high precision. However, how to achieve higher-efficient detection and better integration of the LADAR system for real-time three-dimensional (3D) imaging continues to be a problem. In this study, a novel LADAR system using four linear mode APDs (LmAPDs) is developed for high-efficient detection by adopting a modulation and multiplexing technique. Furthermore, an automatic control system for the array LADAR system is proposed and designed by applying the virtual instrumentation technique. The control system aimsmore » to achieve four functions: synchronization of laser emission and rotating platform, multi-channel synchronous data acquisition, real-time Ethernet upper monitoring, and real-time signal processing and 3D visualization. The structure and principle of the complete system are described in the paper. The experimental results demonstrate that the LADAR system is capable of achieving real-time 3D imaging on an omnidirectional rotating platform under the control of the virtual instrumentation system. The automatic imaging LADAR system utilized only 4 LmAPDs to achieve 256-pixel-per-frame detection with by employing 64-bit demodulator. Moreover, the lateral resolution is ∼15 cm and range accuracy is ∼4 cm root-mean-square error at a distance of ∼40 m.« less
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Orozco, H; Mercado, M A; Morales-Linares, J C; Gómez-Méndez, T J
1996-01-01
The frequency of complications of vagotomy and pyloroplasty for treating peptic disease is considerable. The modification of the Sugiura-Futagawa procedure includes bilateral truncal vagotomy and pyloroplasty as part of the devascularization, with a low frequency of related complications. To study the effects after VP in the outcome of both groups of patients. The results of a retrospective, comparative, not randomized, controlled trial of 153 medical records of patients who underwent our modification of the Sugiura-Futagawa operation (SFO) due to Hemorrhagic Portal Hypertension (HPH), and 100 patients with bilateral truncal vagotomy and pyloroplasty (VP) due to Acid-Peptic Disease (APD) are presented. In both groups VP was done. The first group as part of SFO, and the second to treat their disease. We found 47 complications; 40 (40%) were observed in patients who underwent VP for APD and 7 (4%) in SFO: Post-vagotomy Diarrhea (PVD): 11% after APD and 2% after SFO. Dumping Syndrome (DS): 22% and 1%, and Alkaline Reflux Gastritis (ARG): 7% and 0.5% respectively. The calculated risk of developing complications related to vagotomy and pyloroplasty in peptic ulcer disease was 14 times higher. The incidence of these post VP complications at the SFO group was low (4%), in relation to 40% for the APD; the outcomes were statistically significative (p < 0.05).
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Horiguchi, M; Meltzer, H Y
2013-06-15
Blonanserin is an atypical antipsychotic drug (APD) which, compared to other atypical APDs, is a relatively selective serotonin (5-HT)2A and dopamine D2 antagonist. Comparing blonanserin with more broadly acting atypical APDs could be useful to test the contributions of actions at other monoamine receptors, e.g. 5-HT1A receptors, to the reversal of PCP-induced novel object recognition (NOR) deficit. In this study, we tested the effect of blonanserin alone, and in combination with 5-HT1A agents, on NOR deficit induced by subchronic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP; 2 mg/kg), b.i.d., for 7 days. Blonanserin, 1mg/kg, but not 0.3mg/kg, improved the PCP-induced NOR deficit. However, at 1mg/kg, object exploration was diminished. Co-administration of sub-effective doses of blonanserin (0.3 mg/kg) and the 5-HT1A partial agonist, tandospirone (0.2 mg/kg), significantly reversed the NOR deficit without diminishing activity during the acquisition or retention periods. The combination of WAY100635 (0.6 mg/kg), a 5-HT1A antagonist, and blonanserin (1 mg/kg), also diminished object exploration which prevented assessment of the effect of this combination on NOR. WAY100635 (0.6 mg/kg) blocked the ameliorating effect of risperidone (0.1 mg/kg), another atypical APD with low affinity for 5-HT1A receptors, but did not impair exploration. These results suggest that blonansein and risperidone, atypical APDs which lack a direct action on 5-HT1A receptors require 5-HT1A receptor stimulation to reverse the subchronic PCP-induced NOR deficit and provide a support for clinical trial of blonanserin in combination with tandospirone to ameliorate cognitive impairment in schizophrenia and to have fewer side effects. Copyright © 2013 Elsevier B.V. All rights reserved.
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Gaia16apd - a link between fast and slowly declining type I superluminous supernovae
NASA Astrophysics Data System (ADS)
Kangas, T.; Blagorodnova, N.; Mattila, S.; Lundqvist, P.; Fraser, M.; Burgaz, U.; Cappellaro, E.; Carrasco Martínez, J. M.; Elias-Rosa, N.; Hardy, L. K.; Harmanen, J.; Hsiao, E. Y.; Isern, J.; Kankare, E.; Kołaczkowski, Z.; Nielsen, M. B.; Reynolds, T. M.; Rhodes, L.; Somero, A.; Stritzinger, M. D.; Wyrzykowski, Ł.
2017-07-01
We present ultraviolet (UV), optical and infrared photometry and optical spectroscopy of the type Ic superluminous supernova (SLSN) Gaia16apd (=SN 2016eay), covering its evolution from 26 d before the g-band peak to 234.1 d after the peak. Gaia16apd was followed as a part of the NOT Unbiased Transient Survey (NUTS). It is one of the closest SLSNe known (z = 0.102 ± 0.001), with detailed optical and UV observations covering the peak. Gaia16apd is a spectroscopically typical type Ic SLSN, exhibiting the characteristic blue early spectra with O II absorption, and reaches a peak Mg = -21.8 ± 0.1 mag. However, photometrically it exhibits an evolution intermediate between the fast and slowly declining type Ic SLSNe, with an early evolution closer to the fast-declining events. Together with LSQ12dlf, another SLSN with similar properties, it demonstrates a possible continuum between fast and slowly declining events. It is unusually UV-bright even for an SLSN, reaching a non-K-corrected Muvm2 ≃ -23.3 mag, the only other type Ic SLSN with similar UV brightness being SN 2010gx. Assuming that Gaia16apd was powered by magnetar spin-down, we derive a period of P = 1.9 ± 0.2 ms and a magnetic field of B = 1.9 ± 0.2 × 1014 G for the magnetar. The estimated ejecta mass is between 8 and 16 M⊙, and the kinetic energy between 1.3 and 2.5 × 1052 erg, depending on opacity and assuming that the entire ejecta is swept up into a thin shell. Despite the early photometric differences, the spectra at late times are similar to slowly declining type Ic SLSNe, implying that the two subclasses originate from similar progenitors.
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NASA Astrophysics Data System (ADS)
Yan, Lin; Quimby, R.; Gal-Yam, A.; Brown, P.; Blagorodnova, N.; Ofek, E. O.; Lunnan, R.; Cooke, J.; Cenko, S. B.; Jencson, J.; Kasliwal, M.
2017-05-01
We report the first maximum-light far-ultraviolet (FUV) to near-infrared (NIR) spectra (1000 Å - 1.62 μm, rest) of a hydrogen-poor superluminous supernova, Gaia16apd. At z = 0.1018, it is the second closest and the UV brightest SLSN-I, with 17.4 mag in Swift UVW2 band at -11 days pre-maximum. The coordinated observations with HST, Palomar, and Keck were taken at -2 to +25 days. Assuming an exponential (or t 2) form, we derived the rise time of 33 days and the peak bolometric luminosity of 3 × 1044 erg s-1. At the maximum, the photospheric temperature and velocity are 17,000 K and 14,000 km s-1, respectively. The inferred radiative and kinetic energy are roughly 1 × 1051 and 2 × 1052 erg. Gaia16apd is extremely UV luminous, and emits 50% of its total luminosity at 1000-2500 Å. Compared to the UV spectra (normalized at 3100 Å) of well studied SN1992A (Ia), SN2011fe (Ia), SN1999em (IIP), and SN1993J (IIb), it has orders of magnitude more FUV emission. This excess is interpreted primarily as a result of weaker metal-line blanketing due to a much lower abundance of iron group elements in the outer ejecta. Because these elements originate either from the natal metallicity of the star, or have been newly produced, our observation provides direct evidence that little of these freshly synthesized material, including 56Ni, were mixed into the outer ejecta, and the progenitor metallicity is likely sub-solar. This disfavors Pair-instability Supernova models with helium core masses ≥slant 90 {M}⊙ , where substantial 56Ni material is produced. A higher photospheric temperature definitely contributes to the FUV excess from Gaia16apd. Compared with Gaia16apd, we find PS1-11bam is also UV luminous.
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Dark Current Degradation of Near Infrared Avalanche Photodiodes from Proton Irradiation
NASA Technical Reports Server (NTRS)
Becker, Heidi N.; Johnston, Allan H.
2004-01-01
InGaAs and Ge avalanche photodiodes (APDs) are examined for the effects of 63-MeV protons on dark current. Dark current increases were large and similar to prior results for silicon APDs, despite the smaller size of InGaAs and Ge devices. Bulk dark current increases from displacement damage in the depletion regions appeared to be the dominant contributor to overall dark current degradation. Differences in displacement damage factors are discussed as they relate to structural and material differences between devices.
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Demonstration of Lasercom and Spatial Tracking with a Silicon Geiger-Mode APD Array
2016-02-26
standardized pixel mask as described in the previous paragraph disabling 167 of the 1024 detectors in the array , this gives an absolute maximum rate...number of elements in an array based detector .5 In this paper, we present the results of photon-counting communication tests based on an arrayed ...semiconductor photon-counting detector .6 The array also has the ability to sense the spatial distribution of the received light giving it the potential to act
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The New APD Based Readout for the Crystal Barrel Calorimeter
NASA Astrophysics Data System (ADS)
Urban, M.; Honisch, Ch; Steinacher, M.; CBELSA/TAPS Collaboration
2015-02-01
The CBELSA/TAPS experiment at ELSA measures double polarization observables in meson photoproduction off protons and neutrons. To be able to measure purely neutral reactions off polarized neutrons with high efficiency, the main calorimeter has to be integrated into the first level trigger. This requires to exchange the existing PIN photo diode by a new avalanche photo diode (APD) readout. The newly developed readout electronics will provide an energy resolution compatible to the previous set-up and a fast trigger signal down to 10 MeV energy deposit per crystal. After the successful final tests with a 3x3 CsI crystal matrix in Bonn at ELSA and in Mainz at MAMI all front-end electronics were produced in fall 2013. Automated test routines for the front-end electronics were developed and the characterization measurements of all APDs were successfully accomplished in Bonn. The project is supported by the Deutsche Forschungsgemeinschaft (SFB/TR16) and Schweizerischer Nationalfonds.
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X-ray spectroscopy with silicon pin and avalanche photo diodes
NASA Technical Reports Server (NTRS)
Desai, U. D.
1992-01-01
Results of an evaluation of silicon P-Intrinsic-N (PIN) photodiodes and Avalanche Photodiodes (APD) for the direct detection of soft x rays from 1 to 20 keV and for the detection of scintillation light output from CsI(TI) for higher x ray energies (30 to 1000 keV) are presented. About one keV resolution was achieved at room temperature for both the PIN and APD detectors for soft x rays (1 to 20 keV). Commercially available, low power (18 mV), low noise, hybrid preamplifiers, were used. These photodiodes were also coupled to CsI(TI) scintillator and obtained about 6 resolution at 662 keV. The photodiode frequency response matches well with the emission spectrum of the CsI(TI) scintillator providing good spectral resolution and a higher signal than NaI(TI) when viewed by conventional photomultipliers. A PIN-CsI(TI) combination provides a low energy threshold of around 60 keV while for the APD-CsI(TI) it is 15 keV.
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Analysis of edge density fluctuation measured by trial KSTAR beam emission spectroscopy systema)
NASA Astrophysics Data System (ADS)
Nam, Y. U.; Zoletnik, S.; Lampert, M.; Kovácsik, Á.
2012-10-01
A beam emission spectroscopy (BES) system based on direct imaging avalanche photodiode (APD) camera has been designed for Korea Superconducting Tokamak Advanced Research (KSTAR) and a trial system has been constructed and installed for evaluating feasibility of the design. The system contains two cameras, one is an APD camera for BES measurement and another is a fast visible camera for position calibration. Two pneumatically actuated mirrors were positioned at front and rear of lens optics. The front mirror can switch the measurement between edge and core region of plasma and the rear mirror can switch between the APD and the visible camera. All systems worked properly and the measured photon flux was reasonable as expected from the simulation. While the measurement data from the trial system were limited, it revealed some interesting characteristics of KSTAR plasma suggesting future research works with fully installed BES system. The analysis result and the development plan will be presented in this paper.
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NASA Astrophysics Data System (ADS)
Kubala, S. Z.; Borchardt, M. T.; Den Hartog, D. J.; Holly, D. J.; Jacobson, C. M.; Morton, L. A.; Young, W. C.
2016-11-01
The Thomson scattering diagnostic on MST records both equilibrium and fluctuating electron temperature with a range capability of 10 eV-5 keV. Standard operation with two modified commercial Nd:YAG lasers allows measurements at rates of 1 kHz-25 kHz. Several subsystems of the diagnostic are being improved. The power supplies for the avalanche photodiode detectors (APDs) that record the scattered light are being replaced to improve usability, reliability, and maintainability. Each of the 144 APDs will have an individual rack mounted switching supply, with bias voltage adjustable to match the APD. Long-wavelength filters (1140 nm center, 80 nm bandwidth) have been added to the polychromators to improve capability to resolve non-Maxwellian distributions and to enable directed electron flow measurements. A supercontinuum (SC) pulsed white light source has replaced the tungsten halogen lamp previously used for spectral calibration of the polychromators. The SC source combines substantial brightness produced in nanosecond pulses with a spectrum that covers the entire range of the polychromators.
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Kubala, S Z; Borchardt, M T; Den Hartog, D J; Holly, D J; Jacobson, C M; Morton, L A; Young, W C
2016-11-01
The Thomson scattering diagnostic on MST records both equilibrium and fluctuating electron temperature with a range capability of 10 eV-5 keV. Standard operation with two modified commercial Nd:YAG lasers allows measurements at rates of 1 kHz-25 kHz. Several subsystems of the diagnostic are being improved. The power supplies for the avalanche photodiode detectors (APDs) that record the scattered light are being replaced to improve usability, reliability, and maintainability. Each of the 144 APDs will have an individual rack mounted switching supply, with bias voltage adjustable to match the APD. Long-wavelength filters (1140 nm center, 80 nm bandwidth) have been added to the polychromators to improve capability to resolve non-Maxwellian distributions and to enable directed electron flow measurements. A supercontinuum (SC) pulsed white light source has replaced the tungsten halogen lamp previously used for spectral calibration of the polychromators. The SC source combines substantial brightness produced in nanosecond pulses with a spectrum that covers the entire range of the polychromators.
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HgCdTe APD-based linear-mode photon counting components and ladar receivers
NASA Astrophysics Data System (ADS)
Jack, Michael; Wehner, Justin; Edwards, John; Chapman, George; Hall, Donald N. B.; Jacobson, Shane M.
2011-05-01
Linear mode photon counting (LMPC) provides significant advantages in comparison with Geiger Mode (GM) Photon Counting including absence of after-pulsing, nanosecond pulse to pulse temporal resolution and robust operation in the present of high density obscurants or variable reflectivity objects. For this reason Raytheon has developed and previously reported on unique linear mode photon counting components and modules based on combining advanced APDs and advanced high gain circuits. By using HgCdTe APDs we enable Poisson number preserving photon counting. A metric of photon counting technology is dark count rate and detection probability. In this paper we report on a performance breakthrough resulting from improvement in design, process and readout operation enabling >10x reduction in dark counts rate to ~10,000 cps and >104x reduction in surface dark current enabling long 10 ms integration times. Our analysis of key dark current contributors suggest that substantial further reduction in DCR to ~ 1/sec or less can be achieved by optimizing wavelength, operating voltage and temperature.
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Radiation detection measurements with a new ``Buried Junction'' silicon avalanche photodiode
NASA Astrophysics Data System (ADS)
Lecomte, R.; Pepin, C.; Rouleau, D.; Dautet, H.; McIntyre, R. J.; McSween, D.; Webb, P.
1999-02-01
An improved version of a recently developed "Buried Junction" avalanche photodiode (APD), designed for use with scintillators, is described and characterized. This device, also called the "Reverse APD", is designed to have a wide depletion layer and thus low capacitance, but to have high gain only for e-h pairs generated within the first few microns of the depletion layer. Thus it has high gain for light from scintillators emitting in the 400-600 nm range, with relatively low dark current noise and it is relatively insensitive to minimum ionizing particles (MIPs). An additional feature is that the metallurgical junction is at the back of the wafer, leaving the front surface free to be coupled to a scintillator without fear of junction contamination. The modifications made in this device, as compared with the earlier diode, have resulted in a lower excess noise factor, lower dark current, and much-reduced trapping. The electrical and optical characteristics of this device are described and measurements of energy and timing resolution of this device with several scintillators (BGO, LSO and GSO) of potential interest in high-energy physics and PET imaging systems are presented.
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Remote Patient Management in Automated Peritoneal Dialysis: A Promising New Tool.
Drepper, Valérie Jotterand; Martin, Pierre-Yves; Chopard, Catherine Stoermann; Sloand, James A
2018-01-01
Remote patient management (RPM) has the potential to help clinicians detect early issues, allowing intervention prior to development of more significant problems. A 23-year-old end-stage kidney disease patient required urgent start of renal replacement therapy. A newly available automated peritoneal dialysis (APD) RPM system with cloud-based connectivity was implemented in her care. Pre-defined RPM threshold parameters were set to identify clinically relevant issues. Red flag dashboard alerts heralded prolonged drain times leading to clinical evaluation with subsequent diagnosis of and surgical repositioning for catheter displacement, although it took several days for newly-RPM-exposed staff to recognize this issue. Post-PD catheter repositioning, drain times were again normal as indicated by disappearance of flag alerts and unremarkable cycle volume profiles. Identification of < 90% adherence to prescribed PD therapy was then documented with the RPM system, alerting the clinical staff to address this important issue given its association with significant negative clinical outcomes. Healthcare providers face a "learning curve" to effect optimal utilization of the RPM tool. Larger scale observational studies will determine the impact of RPM on APD technique survival and resource utilization. Copyright © 2018 International Society for Peritoneal Dialysis.
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Novel Photon-Counting Detectors for Free-Space Communication
NASA Technical Reports Server (NTRS)
Krainak, M. A.; Yang, G.; Sun, X.; Lu, W.; Merritt, S.; Beck, J.
2016-01-01
We present performance data for novel photon-counting detectors for free space optical communication. NASA GSFC is testing the performance of two types of novel photon-counting detectors 1) a 2x8 mercury cadmium telluride (HgCdTe) avalanche array made by DRS Inc., and a 2) a commercial 2880-element silicon avalanche photodiode (APD) array. We present and compare dark count, photon-detection efficiency, wavelength response and communication performance data for these detectors. We successfully measured real-time communication performance using both the 2 detected-photon threshold and AND-gate coincidence methods. Use of these methods allows mitigation of dark count, after-pulsing and background noise effects. The HgCdTe APD array routinely demonstrated photon detection efficiencies of greater than 50% across 5 arrays, with one array reaching a maximum PDE of 70%. We performed high-resolution pixel-surface spot scans and measured the junction diameters of its diodes. We found that decreasing the junction diameter from 31 micrometers to 25 micrometers doubled the e- APD gain from 470 for an array produced in the year 2010 to a gain of 1100 on an array delivered to NASA GSFC recently. The mean single-photon SNR was over 12 and the excess noise factors measurements were 1.2-1.3. The commercial silicon APD array exhibited a fast output with rise times of 300 ps and pulse widths of 600 ps. On-chip individually filtered signals from the entire array were multiplexed onto a single fast output.
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Novel Photon-Counting Detectors for Free-Space Communication
NASA Technical Reports Server (NTRS)
Krainak, Michael A.; Yang, Guan; Sun, Xiaoli; Lu, Wei; Merritt, Scott; Beck, Jeff
2016-01-01
We present performance data for novel photon counting detectors for free space optical communication. NASA GSFC is testing the performance of three novel photon counting detectors 1) a 2x8 mercury cadmium telluride avalanche array made by DRS Inc. 2) a commercial 2880 silicon avalanche photodiode array and 3) a prototype resonant cavity silicon avalanche photodiode array. We will present and compare dark count, photon detection efficiency, wavelength response and communication performance data for these detectors. We discuss system wavelength trades and architectures for optimizing overall communication link sensitivity, data rate and cost performance. The HgCdTe APD array has photon detection efficiencies of greater than 50 were routinely demonstrated across 5 arrays, with one array reaching a maximum PDE of 70. High resolution pixel-surface spot scans were performed and the junction diameters of the diodes were measured. The junction diameter was decreased from 31 m to 25 m resulting in a 2x increase in e-APD gain from 470 on the 2010 array to 1100 on the array delivered to NASA GSFC. Mean single photon SNRs of over 12 were demonstrated at excess noise factors of 1.2-1.3.The commercial silicon APD array has a fast output with rise times of 300ps and pulse widths of 600ps. Received and filtered signals from the entire array are multiplexed onto this single fast output. The prototype resonant cavity silicon APD array is being developed for use at 1 micron wavelength.
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Research on APD-based non-line-of-sight UV communication system
NASA Astrophysics Data System (ADS)
Wang, Rongyang; Wang, Ling; Li, Chao; Zhang, Wenjing; Yuan, Yonggang; Xu, Jintong; Zhang, Yan; Li, Xiangyang
2010-10-01
In this paper, specific issues in designing an avalanche photodiode (APD)-based non-line-of-sight (NLOS) ultraviolet (UV) communication system are investigated. A proper wavelength of the UV LEDs and a system configuration should be considered carefully to assure the feasibility of this system. Using the single scattering model, the received optical power at the sensitive area of the APD can be calculated. According to the calculation, it revealed that the scattered ultraviolet signal level was very low; therefore, a post signal processing circuit was necessary. The authors put forward the key components of the circuit based on the compromise between signal bandwidth and gain. The performance of this circuit was evaluated by means of software simulation, and continued work was involved to improve its signal noise ratio (SNR). The transmitter used in this system was 365 nm UV LED array. Strictly speaking, this was not the practical outdoor UV communication system. Since the scattering coefficient of 365 nm UV only drops a little compared with solar blind UV, the research-grade UV communication could be carried out in a darkroom without a great influence. By combining an APD with a compound parabolic concentrator (CPC) optical system, the effective collection area and field of view (FOV) of the detector could be adjusted. Several issues were also raised to improve the performance of UV communication system, including using more powerful UV LEDs and choosing suitable modulation schemes.
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Corrado, Cesare; Zemzemi, Nejib
2018-01-01
Computational models of heart electrophysiology achieved a considerable interest in the medical community as they represent a novel framework for the study of the mechanisms underpinning heart pathologies. The high demand of computational resources and the long computational time required to evaluate the model solution hamper the use of detailed computational models in clinical applications. In this paper, we present a multi-front eikonal algorithm that adapts the conduction velocity (CV) to the activation frequency of the tissue substrate. We then couple the eikonal new algorithm with the Mitchell-Schaeffer (MS) ionic model to determine the tissue electrical state. Compared to the standard eikonal model, this model introduces three novelties: first, it evaluates the local value of the transmembrane potential and of the ionic variable solving an ionic model; second, it computes the action potential duration (APD) and the diastolic interval (DI) from the solution of the MS model and uses them to determine if the tissue is locally re-excitable; third, it adapts the CV to the underpinning electrophysiological state through an analytical expression of the CV restitution and the computed local DI. We conduct series of simulations on a 3D tissue slab and on a realistic heart geometry and compare the solutions with those obtained solving the monodomain equation. Our results show that the new model is significantly more accurate than the standard eikonal model. The proposed model enables the numerical simulation of the heart electrophysiology on a clinical time scale and thus constitutes a viable model candidate for computer-guided radio-frequency ablation. Copyright © 2017 Elsevier B.V. All rights reserved.
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Simulation of Cardiac Arrhythmias Using a 2D Heterogeneous Whole Heart Model
Balakrishnan, Minimol; Chakravarthy, V. Srinivasa; Guhathakurta, Soma
2015-01-01
Simulation studies of cardiac arrhythmias at the whole heart level with electrocardiogram (ECG) gives an understanding of how the underlying cell and tissue level changes manifest as rhythm disturbances in the ECG. We present a 2D whole heart model (WHM2D) which can accommodate variations at the cellular level and can generate the ECG waveform. It is shown that, by varying cellular-level parameters like the gap junction conductance (GJC), excitability, action potential duration (APD) and frequency of oscillations of the auto-rhythmic cell in WHM2D a large variety of cardiac arrhythmias can be generated including sinus tachycardia, sinus bradycardia, sinus arrhythmia, sinus pause, junctional rhythm, Wolf Parkinson White syndrome and all types of AV conduction blocks. WHM2D includes key components of the electrical conduction system of the heart like the SA (Sino atrial) node cells, fast conducting intranodal pathways, slow conducting atriovenctricular (AV) node, bundle of His cells, Purkinje network, atrial, and ventricular myocardial cells. SA nodal cells, AV nodal cells, bundle of His cells, and Purkinje cells are represented by the Fitzhugh-Nagumo (FN) model which is a reduced model of the Hodgkin-Huxley neuron model. The atrial and ventricular myocardial cells are modeled by the Aliev-Panfilov (AP) two-variable model proposed for cardiac excitation. WHM2D can prove to be a valuable clinical tool for understanding cardiac arrhythmias. PMID:26733873
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Wang, Hegui; Chen, Yanhong; Zhu, Hongjun; Wang, Sen; Zhang, Xiwen; Xu, Dongjie; Cao, Kejiang; Zou, Jiangang
2012-01-01
Background Increasing evidence indicates that the rapid component of delayed rectifier potassium current (IKr) is modulated by α- and β-adrenergic stimulation. However, the role and mechanism regulating IKr through β2-adrenoreceptor (β-AR) stimulation in heart failure (HF) are unclear. Methodology/Principal Findings In the present study, we investigated the effects of fenoterol, a highly selective β2-AR agonist, on IKr in left ventricular myocytes obtained from control and guinea pigs with HF induced by descending aortic banding. IKr was measured by using whole cell patch clamp technique. In control myocytes, superfusion of fenoterol (10 µM) caused a 17% decrease in IKr. In HF myocytes, the same concentration of fenoterol produced a significantly greater decrease (33%) in IKr. These effects were not modified by the incubation of myocytes with CGP-20712A, a β1-AR antagonist, but were abolished by pretreatment of myocytes with ICI-118551, a β2-AR antagonist. An inhibitory cAMP analog, Rp-cAMPS and PKA inhibitor significantly attenuated fenoterol-induced inhibition of IKr in HF myocytes. Moreover, fenoterol markedly prolonged action potential durations at 90% (APD90) repolarization in HF ventricular myocytes. Conclusions The results indicate that inhibition of IKr induced by β2-AR stimulation is increased in HF. The inhibitory effect is likely to be mediated through a cAMP/PKA pathway in HF ventricular myocytes. PMID:23029432
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Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease
Lee, An-Sheng; Chen, Wei-Yu; Chan, Hua-Chen; Chung, Ching-Hu; Peng, Hsien-Yu; Chang, Chia-Ming; Su, Ming-Jai; Chen, Chu-Huang; Chang, Kuan-Cheng
2017-01-01
The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD. PMID:28094801
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HgCdTe avalanche photodiodes: A review
NASA Astrophysics Data System (ADS)
Singh, Anand; Srivastav, Vanya; Pal, Ravinder
2011-10-01
This paper presents a comprehensive review of fundamental issues, device architectures, technology development and applications of HgCdTe based avalanche photodiodes (APD). High gain, above 5×10 3, a low excess noise factor close to unity, THz gain-bandwidth product, and fast response in the range of pico-seconds has been achieved by electron-initiated avalanche multiplication for SWIR, MWIR, and LWIR detector applications involving low optical signals. Detector arrays with good element-to-element uniformity have been fabricated paving the way for fabrication of HgCdTe-APD FPAs.
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Effective amplifier noise for an optical receiver based on linear mode avalanche photodiodes
NASA Technical Reports Server (NTRS)
Chen, C.-C.
1989-01-01
The rms noise charge induced by the amplifier for an optical receiver based on the linear-mode avalanche photodiode (APD) was analyzed. It is shown that for an amplifier with a 1-pF capacitor and a noise temperature of 100 K, the rms noise charge due to the amplifier is about 300. Since the noise charge must be small compared to the signal gain, APD gains on the order of 1000 will be required to operate the receiver in the linear mode.
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NASA Astrophysics Data System (ADS)
Hall, Donald
Under a current award, NASA NNX 13AC13G "EXTENDING THE ASTRONOMICAL APPLICATION OF PHOTON COUNTING HgCdTe LINEAR AVALANCHE PHOTODIODE ARRAYS TO LOW BACKGROUND SPACE OBSERVATIONS" UH has used Selex SAPHIRA 320 x 256 MOVPE L-APD HgCdTe arrays developed for Adaptive Optics (AO) wavefront (WF) sensing to investigate the potential of this technology for low background space astronomy applications. After suppressing readout integrated circuit (ROIC) glow, we have placed upper limits on gain normalized dark current of 0.01 e-/sec at up to 8 volts avalanche bias, corresponding to avalanche gain of 5, and have operated with avalanche gains of up to several hundred at higher bias. We have also demonstrated detection of individual photon events. The proposed investigation would scale the format to 1536 x 1536 at 12um (the largest achievable in a standard reticule without requiring stitching) while incorporating reference pixels required at these low dark current levels. The primary objective is to develop, produce and characterize a 1.5k x 1.5k at 12um pitch MOVPE HgCdTe L-APD array, with nearly 30 times the pixel count of the 320 x 256 SAPHIRA, optimized for low background space astronomy. This will involve: 1) Selex design of a 1.5k x 1.5k at 12um pitch ROIC optimized for low background operation, silicon wafer fabrication at the German XFab foundry in 0.35 um 3V3 process and dicing/test at Selex, 2) provision by GL Scientific of a 3-side close-buttable carrier building from the heritage of the HAWAII xRG family, 3) Selex development and fabrication of 1.5k x 1.5k at 12 um pitch MOVPE HgCdTe L-APD detector arrays optimized for low background applications, 4) hybridization, packaging into a sensor chip assembly (SCA) with initial characterization by Selex and, 5) comprehensive characterization of low background performance, both in the laboratory and at ground based telescopes, by UH. The ultimate goal is to produce and eventually market a large format array, the L-APD equivalent of the Teledyne H1RG and H2RG, able to achieve sub-electron read noise and count 1 - 5 um photons with high quantum efficiency and low dark count rate while preserving their Poisson statistics and noise.
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SAPHIRA detector for infrared wavefront sensing
NASA Astrophysics Data System (ADS)
Finger, Gert; Baker, Ian; Alvarez, Domingo; Ives, Derek; Mehrgan, Leander; Meyer, Manfred; Stegmeier, Jörg; Weller, Harald J.
2014-08-01
The only way to overcome the CMOS noise barrier of near infrared sensors used for wavefront sensing and fringe tracking is the amplification of the photoelectron signal inside the infrared pixel by means of the avalanche gain. In 2007 ESO started a program at Selex to develop near infrared electron avalanche photodiode arrays (eAPD) for wavefront sensing and fringe tracking. In a first step the cutoff wavelength was reduced from 4.5 micron to 2.5 micron in order to verify that the dark current scales with the bandgap and can be reduced to less than one electron/ms, the value required for wavefront sensing. The growth technology was liquid phase epitaxy (LPE) with annular diodes based on the loophole interconnect technology. The arrays required deep cooling to 40K to achieve acceptable cosmetic performance at high APD gain. The second step was to develop a multiplexer tailored to the specific application of the GRAVITY instrument wavefront sensors and the fringe tracker. The pixel format is 320x256 pixels. The array has 32 parallel video outputs which are arranged in such a way that the full multiplex advantage is available also for small subwindows. Nondestructive readout schemes with subpixel sampling are possible. This reduces the readout noise at high APD gain well below the subelectron level at frame rates of 1 KHz. The third step was the change of the growth technology from liquid phase epitaxy to metal organic vapour phase epitaxy (MOVPE). This growth technology allows the band structure and doping to be controlled on a 0.1μm scale and provides more flexibility for the design of diode structures. The bandgap can be varied for different layers of Hg(1-x)CdxTe. It is possible to make heterojunctions and apply solid state engineering techniques. The change to MOVPE resulted in a dramatic improvement in the cosmetic quality with 99.97 % operable pixels at an operating temperature of 85K. Currently this sensor is deployed in the 4 wavefront sensors and in the fringe tracker of the VLT instrument GRAVITY. Initial results will be presented. An outlook will be given on the potential of APD technology to be employed in large format near infrared science detectors. Several of the results presented here have also been shown to a different audience at the Scientific Detector Workshop in October 2013 in Florence but this paper has been updated with new results [1].
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Taggart, Peter; Orini, Michele; Hanson, Ben; Hayward, Martin; Clayton, Richard; Dobrzynski, Halina; Yanni, Joseph; Boyett, Mark; Lambiase, Pier D
2014-08-01
Understanding the mechanisms of fatal ventricular arrhythmias is of great importance. In view of the many electrophysiological differences that exist between animal species and humans, the acquisition of basic electrophysiological data in the intact human heart is essential to drive and complement experimental work in animal and in-silico models. Over the years techniques have been developed to obtain basic electrophysiological signals directly from the patients by incorporating these measurements into routine clinical procedures which access the heart such as cardiac catheterisation and cardiac surgery. Early recordings with monophasic action potentials provided valuable information including normal values for the in vivo human heart, cycle length dependent properties, the effect of ischaemia, autonomic nervous system activity, and mechano-electric interaction. Transmural recordings addressed the controversial issue of the mid myocardial "M" cell. More recently, the technique of multielectrode mapping (256 electrodes) developed in animal models has been extended to humans, enabling mapping of activation and repolarisation on the entire left and right ventricular epicardium in patients during cardiac surgery. Studies have examined the issue of whether ventricular fibrillation was driven by a "mother" rotor with inhomogeneous and fragmented conduction as in some animal models, or by multiple wavelets as in other animal studies; results showed that both mechanisms are operative in humans. The simpler spatial organisation of human VF has important implications for treatment and prevention. To link in-vivo human electrophysiological mapping with cellular biophysics, multielectrode mapping is now being combined with myocardial biopsies. This technique enables region-specific electrophysiology changes to be related to underlying cellular biology, for example: APD alternans, which is a precursor of VF and sudden death. The mechanism is incompletely understood but related to calcium cycling and APD restitution. Multielectrode sock mapping during incremental pacing enables epicardial sites to be identified which exhibit marked APD alternans and sites where APD alternans is absent. Whole heart electrophysiology is assessed by activation repolarisation mapping and analysis is performed immediately on-site in order to guide biopsies to specific myocardial sites. Samples are analysed for ion channel expression, Ca(2+)-handling proteins, gap junctions and extracellular matrix. This new comprehensive approach to bridge cellular and whole heart electrophysiology allowed to identify 20 significant changes in mRNA for ion channels Ca(2+)-handling proteins, a gap junction channel, a Na(+)-K(+) pump subunit and receptors (particularly Kir 2.1) between the positive and negative alternans sites. Copyright © 2014 Elsevier Ltd. All rights reserved.
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DOE Office of Scientific and Technical Information (OSTI.GOV)
Kolb, A., E-mail: armin.kolb@med.uni-tuebingen.de; Parl, C.; Liu, C. C.
Purpose: The aim of this study was to develop a prototype PET detector module for a combined small animal positron emission tomography and magnetic resonance imaging (PET/MRI) system. The most important factor for small animal imaging applications is the detection sensitivity of the PET camera, which can be optimized by utilizing longer scintillation crystals. At the same time, small animal PET systems must yield a high spatial resolution. The measured object is very close to the PET detector because the bore diameter of a high field animal MR scanner is limited. When used in combination with long scintillation crystals, thesemore » small-bore PET systems generate parallax errors that ultimately lead to a decreased spatial resolution. Thus, we developed a depth of interaction (DoI) encoding PET detector module that has a uniform spatial resolution across the whole field of view (FOV), high detection sensitivity, compactness, and insensitivity to magnetic fields. Methods: The approach was based on Geiger mode avalanche photodiode (G-APD) detectors with cross-strip encoding. The number of readout channels was reduced by a factor of 36 for the chosen block elements. Two 12 × 2 G-APD strip arrays (25μm cells) were placed perpendicular on each face of a 12 × 12 lutetium oxyorthosilicate crystal block with a crystal size of 1.55 × 1.55 × 20 mm. The strip arrays were multiplexed into two channels and used to calculate the x, y coordinates for each array and the deposited energy. The DoI was measured in step sizes of 1.8 mm by a collimated {sup 18}F source. The coincident resolved time (CRT) was analyzed at all DoI positions by acquiring the waveform for each event and applying a digital leading edge discriminator. Results: All 144 crystals were well resolved in the crystal flood map. The average full width half maximum (FWHM) energy resolution of the detector was 12.8% ± 1.5% with a FWHM CRT of 1.14 ± 0.02 ns. The average FWHM DoI resolution over 12 crystals was 2.90 ± 0.15 mm. Conclusions: The novel DoI PET detector, which is based on strip G-APD arrays, yielded a DoI resolution of 2.9 mm and excellent timing and energy resolution. Its high multiplexing factor reduces the number of electronic channels. Thus, this cross-strip approach enables low-cost, high-performance PET detectors for dedicated small animal PET and PET/MRI and potentially clinical PET/MRI systems.« less
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Long-wavelength photonic integrated circuits and avalanche photodetectors
NASA Astrophysics Data System (ADS)
Tsou, Yi-Jen D.; Zaytsev, Sergey; Pauchard, Alexandre; Hummel, Steve; Lo, Yu-Hwa
2001-10-01
Fast-growing internet traffic volume require high data communication bandwidth over longer distances. Access network bottlenecks put pressure on short-range (SR) telecommunication systems. To effectively address these datacom and telecom market needs, low-cost, high-speed laser modules at 1310 to 1550 nm wavelengths and avalanche photodetectors are required. The great success of GaAs 850nm VCSEls for Gb/s Ethernet has motivated efforts to extend VCSEL technology to longer wavelengths in the 1310 and 1550 nm regimes. However, the technological challenges associated with materials for long wavelength VCSELs are tremendous. Even with recent advances in this area, it is believed that significant additional development is necessary before long wavelength VCSELs that meet commercial specifications will be widely available. In addition, the more stringent OC192 and OC768 specifications for single-mode fiber (SMF) datacom may require more than just a long wavelength laser diode, VCSEL or not, to address numerous cost and performance issues. We believe that photonic integrated circuits (PICs), which compactly integrate surface-emitting lasers with additional active and passive optical components with extended functionality, will provide the best solutions to today's problems. Photonic integrated circuits have been investigated for more than a decade. However, they have produced limited commercial impact to date primarily because the highly complicated fabrication processes produce significant yield and device performance issues. In this presentation, we will discuss a new technology platform of InP-based PICs compatible with surface-emitting laser technology, as well as a high data rate externally modulated laser module. Avalanche photodetectors (APDs) are the key component in the receiver to achieve high data rate over long transmission distance because of their high sensitivity and large gain- bandwidth product. We have used wafer fusion technology to achieve InGaAs/Si APDs with much greater potential than the traditional InGaAs/InP APDs. Preliminary results on their performance will be presented.
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Ahmmed, Ansar Uddin
2017-10-01
To compare the sensitivity and specificity of Auditory Figure Ground sub-tests of the SCAN-3 battery, using signal to noise ratio (SNR) of +8 dB (AFG+8) and 0 dB (AFG0), in identifying auditory processing disorder (APD). A secondary objective was to evaluate any difference in auditory processing (AP) between children with symptoms of inattention versus combined sub-types of Attention Deficit Hyperactivity Disorder (ADHD). Data from 201 children, aged 6 to 16 years (mean: 10 years 6 months, SD: 2 years 8 months), who were assessed for suspected APD were reviewed retrospectively. The outcomes of the SCAN-3 APD test battery, Swanson Nolan and Pelham-IV parental rating (SNAP-IV) and Children's Communication Checklist-2 (CCC-2) were analysed. AFG0 had a sensitivity of 56.3% and specificity of 100% in identifying children performing poorly in at least two of six SCAN-3 sub-tests or one of the two questionnaires, in contrast to 42.1% and 80% respectively for AFG+8. Impaired AP was mostly associated with symptoms of ADHD and /or language impairment (LI). LI was present in 92.9% of children with ADHD symptoms. Children with symptoms of combined ADHD plus LI performed significantly poorly (p < 0.05) compared to inattention ADHD plus LI in Filtered Words (FW) sub-test, but not in the rest of the SCAN-3 sub-tests. Speech in noise tests using SNR of 0 dB is better than +8 dB in assessing APD. The better FW performance of the inattention ADHD plus LI group can be speculated to be related to known difference in activity in a neural network between different sub-types of ADHD. The findings of the study and existing literature suggest that neural networks connecting the cerebral hemispheres, basal ganglia and cerebellum are involved in APD, ADHD and LI. Copyright © 2017 Elsevier B.V. All rights reserved.
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2012-01-01
Background This study examines the patients' need for information and guidance in the selection of dialysis modality, and in establishing and practicing home dialysis. The study focuses on patients' experiences living with home dialysis, how they master the treatment, and their views on how to optimize communication with health services and the potential of telemedicine. Methods We used an inductive research strategy and conducted semi-structured interviews with eleven patients established in home dialysis. Our focus was the patients' experiences with home dialysis, and our theoretical reference was patients' empowerment through telemedicine solutions. Three informants had home haemodialysis (HHD); eight had peritoneal dialysis (PD), of which three had automated peritoneal dialysis (APD); and five had continuous ambulatory peritoneal dialysis (CAPD). The material comprises all PD-patients in the catchment area capable of being interviewed, and all known HHD-users in Norway at that time. Results All of the interviewees were satisfied with their choice of home dialysis, and many experienced a normalization of daily life, less dominated by disease. They exhibited considerable self-management skills and did not perceive themselves as ill, but still required very close contact with the hospital staff for communication and follow-up. When choosing a dialysis modality, other patients' experiences were often more influential than advice from specialists. Information concerning the possibility of having HHD, including knowledge of how to access it, was not easily available. Especially those with dialysis machines, both APD and HHD, saw a potential for telemedicine solutions. Conclusions As home dialysis may contribute to a normalization of life less dominated by disease, the treatment should be organized so that the potential for home dialysis can be fully exploited. Pre-dialysis information should be unbiased and include access to other patients' experiences. Telemedicine may potentially facilitate a communication-based follow-up and improve safety within the home setting, making it easier to choose and live with home dialysis. PMID:22429705
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Determinants of ante-partum depression: a multicenter study.
Balestrieri, Matteo; Matteo, Balestrieri; Isola, Miriam; Miriam, Isola; Bisoffi, Giulia; Giulia, Bisoffi; Calò, Salvatore; Salvatore, Calò; Conforti, Anita; Anita, Conforti; Driul, Lorenza; Lorenza, Driul; Marchesoni, Diego; Diego, Marchesoni; Petrosemolo, Paola; Paola, Petrosemolo; Rossi, Michela; Michela, Rossi; Zito, Adriana; Adriana, Zito; Zorzenone, Stefania; Stefania, Zorzenone; Di Sciascio, Guido; Guido, Di Sciascio; Leone, Roberto; Roberto, Leone; Bellantuono, Cesario; Cesario, Bellantuono
2012-12-01
Ante-partum depression (APD) is usually defined as a non-psychotic depressive episode of mild to moderate severity, beginning in or extending into pregnancy. APD has received less attention than postpartum depression. This is a cross-sectional study carried out in the Obstetrics and Gynaecology (OG) departments of four different general hospitals in Italy. Women attending consecutively the OG departments for their first ultrasound examination were asked to fill in the Edinburgh Postnatal Depression Scale (EPDS) in its Italian validated version. We used the total scores of the EPDS as a continuous variable for univariate and linear regression analyses; in accordance with the literature, the item analysis of EPDS was carried out by classifying the sample as women with "no depression" (scores 0-9), "possible depression" (scores 10-12), "probable depression" (scores 13+) and "probable APD" (scores 15+). The number of women recruited was 1,608. The EPDS assessment classified 10.9 % of the women as possibly depressed, 8.3 % as probably depressed and 4.7 % probably affected from an APD. EPDS score distribution was associated with nationality (higher scores for foreigners), cohabitation (higher scores for women living with friends or in a community), occupation (higher scores for housewives), past episodes of depression and use of herbal drugs. Non-depressed women had significantly lower values on all ten items as compared with depressed women, however, the pattern of item distribution on the EPDS scale remained similar across depression severity groups. In all four groups item 4 (anxious depression) attained the highest scores, while item 10 (suicidality) attained the lowest scores.
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NASA Astrophysics Data System (ADS)
Finger, G.; Baker, I.; Downing, M.; Alvarez, D.; Ives, D.; Mehrgan, L.; Meyer, M.; Stegmeier, J.; Weller, H. J.
2017-11-01
Large format near infrared HgCdTe 2Kx2K and 4Kx4K MBE arrays have reached a level of maturity which meets most of the specifications required for near infrared (NIR) astronomy. The only remaining problem is the persistence effect which is device specific and not yet fully under control. For ground based multi-object spectroscopy on 40 meter class telescopes larger pixels would be advantageous. For high speed near infrared fringe tracking and wavefront sensing the only way to overcome the CMOS noise barrier is the amplification of the photoelectron signal inside the infrared pixel by means of the avalanche gain. A readout chip for a 320x256 pixel HgCdTe eAPD array will be presented which has 32 parallel video outputs being arranged in such a way that the full multiplex advantage is also available for small sub-windows. In combination with the high APD gain this allows reducing the readout noise to the subelectron level by applying nondestructive readout schemes with subpixel sampling. Arrays grown by MOVPE achieve subelectron readout noise and operate with superb cosmetic quality at high APD gain. Efforts are made to reduce the dark current of those arrays to make this technology also available for large format focal planes of NIR instruments offering noise free detectors for deep exposures. The dark current of the latest MOVPE eAPD arrays is already at a level adequate for noiseless broad and narrow band imaging in scientific instruments.