Mechanism for Amplitude Alternans in Electrocardiograms and the Initiation of Spatiotemporal Chaos

NASA Astrophysics Data System (ADS)

Chen, Diandian Diana; Gray, Richard A.; Uzelac, Ilija; Herndon, Conner; Fenton, Flavio H.

2017-04-01

It is widely believed that one major life-threatening transition to chaotic fibrillation occurs via spiral-wave breakup that is preceded by spatiotemporal dispersion of refractoriness due to alternations in the duration of the cardiac action potential (AP). However, recent clinical and experimental evidence suggests that other characteristics of the AP may contribute to, and perhaps drive, this dangerous dynamical instability. To identify the relative roles of AP characteristics, we performed experiments in rabbit hearts under conditions to minimize AP duration dynamics which unmasked pronounced AP amplitude alternans just before the onset of fibrillation. We used a simplified ionic cell model to derive a return map and a stability condition that elucidates a novel underlying mechanism for AP alternans and spiral breakup. We found that inactivation of the sodium current is key to developing amplitude alternans and is directly connected to conduction block and initiation of arrhythmias. Simulations in 2D where AP amplitude alternation led to turbulence confirm our hypothesis.

Changes in extracellular pH and myocardial ischaemia alter the cardiac effects of diadenosine tetraphosphate and pentaphosphate

PubMed Central

Stavrou, Brigitte M; Beck, Caroline; Flores, Nicholas A

2001-01-01

The structural conformation of diadenosine tetraphosphate (Ap4A) and pentaphosphate (Ap5A) has been reported to alter as pH is reduced. As such, it is possible that the cardiac effects of Ap4A and Ap5A vary during acidosis and myocardial ischaemia due to changes in ligand structure, receptor proteins or intracellular signalling. We investigated whether the cardiac electrophysiological and coronary vasomotor effects of Ap4A and Ap5A are preserved under conditions of extracellular acidosis (pH 6.5) and alkalosis (pH 8.5) and whether Ap4A has any electrophysiological or antiarrhythmic effects during ischaemia. Transmembrane right ventricular action potentials, refractory periods and coronary perfusion pressure were recorded from isolated, Langendorff-perfused guinea-pig hearts under constant flow conditions. The effects of 1 nM and 1 μM Ap4A and Ap5A were studied at pH 7.4, 6.5 and 8.5. The effects of 1 μM Ap4A were studied during global low-flow ischaemia and reperfusion. At pH 7.4, Ap4A and Ap5A increased action potential duration (APD95) and refractory period (RP) and reduced coronary perfusion pressure. The electrophysiological effects were absent at pH 6.5 while the reductions in perfusion pressure were attenuated. At pH 8.5, Ap4A increased RP but the effects of Ap4A and Ap5A on perfusion pressure were attenuated. During ischaemia, Ap4A had no antiarrhythmic or electrophysiological effects. These data demonstrate the importance of extracellular pH in influencing the effects of Ap4A and Ap5A on the heart and indicate that any potentially cardioprotective effects of these compounds during normal perfusion at physiological pH are absent during ischaemia. PMID:11588119

Effect of knockout of α2δ-1 on action potentials in mouse sensory neurons.

PubMed

Margas, Wojciech; Ferron, Laurent; Nieto-Rostro, Manuela; Schwartz, Arnold; Dolphin, Annette C

2016-08-05

Gene deletion of the voltage-gated calcium channel auxiliary subunit α2δ-1 has been shown previously to have a cardiovascular phenotype, and a reduction in mechano- and cold sensitivity, coupled with delayed development of neuropathic allodynia. We have also previously shown that dorsal root ganglion (DRG) neuron calcium channel currents were significantly reduced in α2δ-1 knockout mice. To extend our findings in these sensory neurons, we have examined here the properties of action potentials (APs) in DRG neurons from α2δ-1 knockout mice in comparison to their wild-type (WT) littermates, in order to dissect how the calcium channels that are affected by α2δ-1 knockout are involved in setting the duration of individual APs and their firing frequency. Our main findings are that there is reduced Ca(2+) entry on single AP stimulation, particularly in the axon proximal segment, reduced AP duration and reduced firing frequency to a 400 ms stimulation in α2δ-1 knockout neurons, consistent with the expected role of voltage-gated calcium channels in these events. Furthermore, lower intracellular Ca(2+) buffering also resulted in reduced AP duration, and a lower frequency of AP firing in WT neurons, mimicking the effect of α2δ-1 knockout. By contrast, we did not obtain any consistent evidence for the involvement of Ca(2+)-activation of large conductance calcium-activated potassium (BK) and small conductance calcium-activated potassium (SK) channels in these events. In conclusion, the reduced Ca(2+) elevation as a result of single AP stimulation is likely to result from the reduced duration of the AP in α2δ-1 knockout sensory neurons.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. © 2016 The Authors.

Human stem cell-derived cardiomyocytes detect drug-mediated changes in action potentials and ion currents.

PubMed

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.

Comprehensive Analyses of Ventricular Myocyte Models Identify Targets Exhibiting Favorable Rate Dependence

PubMed Central

Bugana, Marco; Severi, Stefano; Sobie, Eric A.

2014-01-01

Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP). The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD) antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz) and fast (2 Hz) rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, rate-dependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal rate-dependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of AP duration rate dependence, and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs. PMID:24675446

Comprehensive analyses of ventricular myocyte models identify targets exhibiting favorable rate dependence.

PubMed

Cummins, Megan A; Dalal, Pavan J; Bugana, Marco; Severi, Stefano; Sobie, Eric A

2014-03-01

Reverse rate dependence is a problematic property of antiarrhythmic drugs that prolong the cardiac action potential (AP). The prolongation caused by reverse rate dependent agents is greater at slow heart rates, resulting in both reduced arrhythmia suppression at fast rates and increased arrhythmia risk at slow rates. The opposite property, forward rate dependence, would theoretically overcome these parallel problems, yet forward rate dependent (FRD) antiarrhythmics remain elusive. Moreover, there is evidence that reverse rate dependence is an intrinsic property of perturbations to the AP. We have addressed the possibility of forward rate dependence by performing a comprehensive analysis of 13 ventricular myocyte models. By simulating populations of myocytes with varying properties and analyzing population results statistically, we simultaneously predicted the rate-dependent effects of changes in multiple model parameters. An average of 40 parameters were tested in each model, and effects on AP duration were assessed at slow (0.2 Hz) and fast (2 Hz) rates. The analysis identified a variety of FRD ionic current perturbations and generated specific predictions regarding their mechanisms. For instance, an increase in L-type calcium current is FRD when this is accompanied by indirect, rate-dependent changes in slow delayed rectifier potassium current. A comparison of predictions across models identified inward rectifier potassium current and the sodium-potassium pump as the two targets most likely to produce FRD AP prolongation. Finally, a statistical analysis of results from the 13 models demonstrated that models displaying minimal rate-dependent changes in AP shape have little capacity for FRD perturbations, whereas models with large shape changes have considerable FRD potential. This can explain differences between species and between ventricular cell types. Overall, this study provides new insights, both specific and general, into the determinants of AP duration rate dependence, and illustrates a strategy for the design of potentially beneficial antiarrhythmic drugs.

Clinical assessment and three-dimensional movement analysis: An integrated approach for upper limb evaluation in children with unilateral cerebral palsy

PubMed Central

Ortibus, Els; Simon-Martinez, Cristina; Desloovere, Kaat; Molenaers, Guy; Klingels, Katrijn; Feys, Hilde

2017-01-01

Introduction The clinical application of upper limb (UL) three-dimensional movement analysis (3DMA) in children with unilateral cerebral palsy (uCP) remains challenging, despite its benefits compared to conventional clinical scales. Moreover, knowledge on UL movement pathology and how this relates to clinical parameters remains scarce. Therefore, we investigated UL kinematics across different manual ability classification system (MACS) levels and explored the relation between clinical and kinematic parameters in children with uCP. Patients and methods Fifty children (MACS: I = 15, II = 26, III = 9) underwent an UL evaluation of sensorimotor impairments (grip force, muscle strength, muscle tone, two-point discrimination, stereognosis), bimanual performance (Assisting Hand Assessment, AHA), unimanual capacity (Melbourne Assessment 2, MA2) and UL-3DMA during hand-to-head, hand-to-mouth and reach-to-grasp tasks. Global parameters (Arm Profile Score (APS), duration, (timing of) maximum velocity, trajectory straightness) and joint specific parameters (angles at task endpoint, ROM and Arm Variable Scores (AVS)) were extracted. The APS and AVS refer respectively to the total amount of movement pathology and movement deviations of wrist, elbow, shoulder, scapula and trunk. Results Longer movement durations and increased APS were found with higher MACS-levels (p<0.001). Increased APS was also associated with more severe sensorimotor impairments (r = -0.30-(-0.73)) and with lower AHA and MA2-scores (r = -0.50-(-0.86)). For the joint specific parameters, stronger movement deviations distally were significantly associated with increased muscle weakness (r = -0.32-(-0.74)) and muscle tone (r = 0.33-(-0.61)); proximal movement deviations correlated only with muscle weakness (r = -0.35–0.59). Regression analysis exposed grip force as the most important predictor for the variability in APS (p<0.002). Conclusion We found increased movement pathology with increasing MACS-levels and demonstrated the adverse impact of especially muscle weakness. The lower correlations suggest that 3DMA provides additional information regarding UL motor function, particularly for the proximal joints. Integrating both methods seems clinically meaningful to obtain a comprehensive representation of all aspects of a child’s UL functioning. PMID:28671953

Clinical assessment and three-dimensional movement analysis: An integrated approach for upper limb evaluation in children with unilateral cerebral palsy.

PubMed

Mailleux, Lisa; Jaspers, Ellen; Ortibus, Els; Simon-Martinez, Cristina; Desloovere, Kaat; Molenaers, Guy; Klingels, Katrijn; Feys, Hilde

2017-01-01

The clinical application of upper limb (UL) three-dimensional movement analysis (3DMA) in children with unilateral cerebral palsy (uCP) remains challenging, despite its benefits compared to conventional clinical scales. Moreover, knowledge on UL movement pathology and how this relates to clinical parameters remains scarce. Therefore, we investigated UL kinematics across different manual ability classification system (MACS) levels and explored the relation between clinical and kinematic parameters in children with uCP. Fifty children (MACS: I = 15, II = 26, III = 9) underwent an UL evaluation of sensorimotor impairments (grip force, muscle strength, muscle tone, two-point discrimination, stereognosis), bimanual performance (Assisting Hand Assessment, AHA), unimanual capacity (Melbourne Assessment 2, MA2) and UL-3DMA during hand-to-head, hand-to-mouth and reach-to-grasp tasks. Global parameters (Arm Profile Score (APS), duration, (timing of) maximum velocity, trajectory straightness) and joint specific parameters (angles at task endpoint, ROM and Arm Variable Scores (AVS)) were extracted. The APS and AVS refer respectively to the total amount of movement pathology and movement deviations of wrist, elbow, shoulder, scapula and trunk. Longer movement durations and increased APS were found with higher MACS-levels (p<0.001). Increased APS was also associated with more severe sensorimotor impairments (r = -0.30-(-0.73)) and with lower AHA and MA2-scores (r = -0.50-(-0.86)). For the joint specific parameters, stronger movement deviations distally were significantly associated with increased muscle weakness (r = -0.32-(-0.74)) and muscle tone (r = 0.33-(-0.61)); proximal movement deviations correlated only with muscle weakness (r = -0.35-0.59). Regression analysis exposed grip force as the most important predictor for the variability in APS (p<0.002). We found increased movement pathology with increasing MACS-levels and demonstrated the adverse impact of especially muscle weakness. The lower correlations suggest that 3DMA provides additional information regarding UL motor function, particularly for the proximal joints. Integrating both methods seems clinically meaningful to obtain a comprehensive representation of all aspects of a child's UL functioning.

Effects of attention bias modification with short and long stimulus-duration: A randomized experiment with individuals with subclinical social anxiety.

PubMed

Liang, Chi-Wen; Hsu, Wen-Yau

2016-06-30

This study investigated the differential effects of two attention bias modification (ABM) with different stimulus durations. Seventy-two undergraduates with subclinical social anxiety were randomly assigned to one of four conditions: an ABM condition with either a 100-ms or a 500-ms stimulus duration (ABM-100/ ABM-500) or an attention placebo (AP) condition with either a 100-ms or a 500-ms stimulus duration (AP-100/ AP-500). Participants completed the pre-assessments, eight attentional training sessions, and post-assessments. A modified Posner paradigm was used to assess changes in attentional processing. After completion of attentional training, the ABM-100 group significantly speeded up their responses to 100-ms invalid trials, regardless of the word type. The ABM-100 group also exhibited significant reduced latencies to 500-ms invalid social threat trials and a marginally significant reduced latencies to 500-ms invalid neutral trials. The ABM-500 group showed significant reduced latencies to 500-ms invalid social threat trials. Both ABMs significantly reduced participants' fear of negative evaluations and interactional anxiousness relative to their comparative AP. The effects on social anxiety did not differ between the two ABMs. This study suggests that although both ABMs using short and long stimulus durations reduce some aspects of social anxiety, they influence participants' attentional disengagement in different ways. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

[Interaction between quality and duration of sleep on the prevalence of type 2 diabetes].

PubMed

Zhang, Pan; Lou, Peian; Chang, Guiqiu; Zhang, Lei; Chen, Peipei; Li, Ting; Qiao, Cheng; Dong, Zongmei

2014-09-01

To explore the effects related to quality and duration of sleep and their interactions on the prevalence of type-2 diabetes (T2DM). 9 622 people aged 18 years and over were recruited for our cross-sectional study during March 2013 to May 2013. Unconditional logistic regression was used to analyze the relationship between quality and duration of sleep on T2DM. Bootstrap was used to calculate the relative excess risk of interaction (RERI), the attributable proportion (AP) of interaction and the synergy index (SI). 95% confidence intervals (CI) of RERI, AP and SI were estimated. Concerning the comparison between cases and controls on both individual and total scores, other scores were all significantly different (P < 0.01), except for two items (time for falling asleep and drugs for hypnosis). The prevalence of T2DM in volunteers with poor sleeping quality was higher than that in volunteers with good sleeping quality (P < 0.01). Individuals with sleep duration <6 hours had a higher prevalence of T2DM, when compared with individuals with sleep duration of 6-8 hours (P < 0.01). After adjusting for age, gender, level of education, occupation, family history of diabetes, status on cigarette smoking, alcohol intake, physical activities and body mass index (BMI), the prevalence of T2DM appeared the highest in those with poor sleeping quality and short duration (OR = 4.78, 95% CI:3.32-6.99; P < 0.01), when compared with those who had good sleep quality and 6-8 h sleep duration. The risk of T2DM still increased in people who had poor sleep or long duration (OR = 1.92, 95% CI:1.18-3.31; P < 0.01). Values of RERI, AP and SI (with 95% CI) were 2.33 (1.23-8.79), 0.67(0.21-0.83) and 6.87 (2.33-10.75), respectively, for the interaction between poor sleep quality and short sleep duration, while 0.33 (-0.12-1.13), 0.17 (-0.03-0.51), 1.56 (0.76-2.74) for the interaction between good sleep quality and long sleep duration. Our results suggested that there were additive interactions between poor quality and shorter duration of sleep.

NS5806 partially restores action potential duration but fails to ameliorate calcium transient dysfunction in a computational model of canine heart failure.

PubMed

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.

Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour.

PubMed

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.

Serum creatinine and albumin decline predict the contraction of nosocomial aspiration pneumonia in patients undergoing hemodialysis.

PubMed

Minakuchi, Hitoshi; Wakino, Shu; Hayashi, Koichi; Inamoto, Hajime; Itoh, Hiroshi

2014-08-01

Aspiration pneumonia (AP) is prevalent in older adults and the hemodialysis (HD) population has been getting older. Therefore, it is speculated that increasing number of HD patients would suffer from AP. However, the clinical aspects of AP in HD patients have not been elucidated. Consecutive HD patients with nosocomial AP hospitalized in our university hospital from April 2007 to December 2008 were recruited. Their clinical characteristics, risk factors for contraction, and the fatality of AP and treatment options were described. Nineteen out of 356 hospitalized HD patients had AP and 8 out of 19 AP patients died, indicating the incidence rate and fatality rate were 5.34% and 42.1%, respectively. Multiple regression analysis revealed that the risk factors for contracting AP included age, body mass index, serum creatinine levels (Cre) and the monthly decline rate of Cre. It also revealed that serum albumin (Alb) and basal total cholesterol levels, the decline rate of Alb and Cre levels, and the duration of AP were independent risk factors for fatality. Survivors were most often treated with tube feeding. Both contraction rate and fatality of nosocomial AP were high among HD patients. Both the malnutrition as well as the decline rate for nutrition and muscle volume indicated by falls in Alb and Cre, respectively, had clinical relevance in AP. Maintaining nutritional state by tube feeding and muscle volume seems to be the mainstay for the prevention and the treatment of AP in HD patients. © 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.

Angiotensin II and angiotensin II receptor blocker modulate the arrhythmogenic activity of pulmonary veins.

PubMed

Chen, Yi-Jen; Chen, Yao-Chang; Tai, Ching-Tai; Yeh, Hung-I; Lin, Cheng-I; Chen, Shih-Ann

2006-01-01

Angiotensin II receptor blockers (AIIRBs) have been shown to prevent atrial fibrillation. The pulmonary veins (PVs) are the most important focus for the generation of atrial fibrillation. The aim of this study was to evaluate whether angiotensin II or AIIRB may change the arrhythmogenic activity of the PVs. Conventional microelectrodes and whole-cell patch clamps were used to investigate the action potentials (APs) and ionic currents in isolated rabbit PV tissue and single cardiomyocytes before and after administering angiotensin II or losartan (AIIRB). In the tissue preparations, angiotensin II induced delayed after-depolarizations (1, 10, and 100 nM) and accelerated the automatic rhythm (10 and 100 nM). Angiotensin II (100 nM) prolonged the AP duration and increased the contractile force (10 and 100 nM). Losartan (1 and 10 microM) inhibited the automatic rhythm. Losartan (10 microM) prolonged the AP duration and reduced the contractile force (1 and 10 microM). Angiotensin II reduced the transient outward potassium current (I(to)) but increased the L-type calcium, delayed rectifier potassium (I(K)), transient inward (I(ti)), pacemaker, and Na(+)-Ca(2+) exchanger (NCX) currents in the PV cardiomyocytes. Losartan decreased the I(to), I(K), I(ti), and NCX currents. In conclusion, angiotensin II and AIIRB modulate the PV electrical activity, which may play a role in the pathophysiology of atrial fibrillation.

LaAP2L1, a heterosis-associated AP2/EREBP transcription factor of Larix, increases organ size and final biomass by affecting cell proliferation in Arabidopsis.

PubMed

Li, Ai; Zhou, Yanan; Jin, Chuan; Song, Wenqin; Chen, Chengbin; Wang, Chunguo

2013-11-01

In Larix and in some crops, heterosis is prevalent and has been widely used in breeding to produce excellent varieties. However, the molecular basis of heterosis in Larix remains ambiguous. LaAP2L1, a member of the AP2/EREBP transcription factor family, has been suggested to be involved in heterosis in Larix hybrids. Here, the function and regulation of LaAP2L1 were further explored. Overexpression of LaAP2L1 led to markedly enlarged organs and heterosis-like traits in Arabidopsis. Fresh weight of leaves was almost twice as great as in vector controls. Likewise, seed yield of 35S::LaAP2L1 individual plants was >200% greater than that of control plants. The enlarged organs and heterosis-like traits displayed by 35S::LaAP2L1 plants were mainly due to enhanced cell proliferation and prolonged growth duration. At the molecular level, LaAP2L1 upregulated the expression of ANT, EBP1, and CycD3;1 and inhibited the expression of ARGOS in 35S::LaAP2L1 plants, suggesting an important molecular role of LaAP2L1 in regulating plant organ development. These findings provide new insights into the formation of heterosis in woody plants and suggest that LaAP2L1 has potential applications in breeding high-yielding crops and energy plants. In addition, 50 AP2/EREBP transcription factors, including LaAP2L1, in Larix were identified by transcriptome sequencing, and phylogenetic analysis was conducted. This provided information that will be important in further revealing the functions of these transcription factors.

Comparative hemodynamic effects of hypotension induced by diadenosine tetraphosphate (AP4A) and ATP in dogs.

PubMed

Takeda, Shohei; Inada, Yutaka; Fukui, Noriyuki; Tomaru, Teruaki

1997-03-01

ATP and diadenosine tetraphosphate (AP 4 A) have been shown to produce vasodilation mediated by P 1 - and P 2 -purinoceptor, respectively. The differing mechanisms involved in this vasodilating activity may induce different systemic hemodynamic changes. We compared the hemodynamic effects of AP 4 A-induced hypotension with those induced by ATP. Fourteen mongrel dogs were anesthetized with 0.87% halothane in oxygen (1 MAC). After the baseline period, mean arterial pressure was reduced to 60 mmHg for 60 min by the infusion of AP 4 A or ATP. The ATP- and AP 4 A-induced hypotension resulted in a maximum reduction in systemic vascular resistance of 43% and 46%, respectively (P<0.01), associated with a significant increase in stroke volume index. With ATP, a 20% of maximum increase (P<0.05) in cardiac index (CI) was observed during the induced hypotension. In contrast, AP 4 A-induced hypotension did not result in any changes in CI throughout the observation period. The varying results concerning CI during the ATP- and AP 4 A-induced hypotension were probably due to differences in ventricular filling pressure, since AP 4 A-induced hypotension was associated with decreases (P<0.01) in both right atrial and pulmonary capillary wedge pressures, whereas neither of these variables significantly changed with ATP. The hypotension induced by either ATP or AP 4 A was associated with a significant decrease in heart rate (HR). However, both the magnitude and duration of decreases in HR due to ATP-induced hypotension were more pronounced than those seen with AP 4 A. In conclusion, while both drugs were equally capable of inducing hypotension, our results suggest that AP 4 A was more suitable for induced hypotension because of its potent vasodilatory action with venodilation and less negative chronotropic action.

Recovery of the vomiting reflex following area postrema ablation in squirrel monkeys

NASA Technical Reports Server (NTRS)

Elfar, S.; Brizzee, Kenneth R.; Fox, Robert A.; Corcoran, Meryl Lee; Daunton, Nancy G.; Coleman, J.

1991-01-01

The role of the area postrema (AP) in motion-induced emesis was re-assessed recently in several different species. In a few of these studies, the role of the AP in motion-induced conditioned taste aversion (CTA) was also addressed. The purpose was to extend this comparative study to the squirrel monkey, to evaluate further the role of AP in vomiting, and to investigate the dynamics of the recovery process. The AP was ablated bilaterally in 7 motion-susceptible squirrel monkeys which previously had been characterized in terms of their responses to various motion sickness-inducing stimuli. After recovery from surgery all animals were tested at 30-day intervals for a period of 11 months to determine the effects of AP ablations on susceptibility to the same sickness-inducing conditions. In addition, the effectiveness of motion in preducing CTA was evaluated. All pre-ablation motion tests involved stimulation for 30 min., while post-lesion tests were 60 min., in duration. All animals showed significant increases in latencies to vomiting after AP ablations. However, the latencies tended to decrease with time after ablation. All but one animal vomited on at least one of the 10 motion tests occurring after ablation of AP. In addition, CTA was produced by motion used in the conditioning sessions. These results suggest that structures other than AP, and processes other that those mediated through AP, may play an important role in motion-induced emesis.

Impact of ionic current variability on human ventricular cellular electrophysiology.

PubMed

Romero, Lucía; Pueyo, Esther; Fink, Martin; Rodríguez, Blanca

2009-10-01

Abnormalities in repolarization and its rate dependence are known to be related to increased proarrhythmic risk. A number of repolarization-related electrophysiological properties are commonly used as preclinical biomarkers of arrhythmic risk. However, the variability and complexity of repolarization mechanisms make the use of cellular biomarkers to predict arrhythmic risk preclinically challenging. Our goal is to investigate the role of ionic current properties and their variability in modulating cellular biomarkers of arrhythmic risk to improve risk stratification and identification in humans. A systematic investigation into the sensitivity of the main preclinical biomarkers of arrhythmic risk to changes in ionic current conductances and kinetics was performed using computer simulations. Four stimulation protocols were applied to the ten Tusscher and Panfilov human ventricular model to quantify the impact of +/-15 and +/-30% variations in key model parameters on action potential (AP) properties, Ca(2+) and Na(+) dynamics, and their rate dependence. Simulations show that, in humans, AP duration is moderately sensitive to changes in all repolarization current conductances and in L-type Ca(2+) current (I(CaL)) and slow component of the delayed rectifier current (I(Ks)) inactivation kinetics. AP triangulation, however, is strongly dependent only on inward rectifier K(+) current (I(K1)) and delayed rectifier current (I(Kr)) conductances. Furthermore, AP rate dependence (i.e., AP duration rate adaptation and restitution properties) and intracellular Ca(2+) and Na(+) levels are highly sensitive to both I(CaL) and Na(+)/K(+) pump current (I(NaK)) properties. This study provides quantitative insights into the sensitivity of preclinical biomarkers of arrhythmic risk to variations in ionic current properties in humans. The results show the importance of sensitivity analysis as a powerful method for the in-depth validation of mathematical models in cardiac electrophysiology.

Induced Pacemaker Activity on Toad Skin

PubMed Central

Bueno, Enrique J.; Corchs, Lelio

1968-01-01

The electrical transients produced on the isolated abdominal skin obtained from Bufo arenarum Hensel, under the influence of inward current pulses of constant intensity have been studied. When both faces of the skin are bathed with Ringer's solution, short pulses of inward current give rise to transient variations of the potential difference between both faces of the skin with "all-or-nothing" characteristics (action potentials, AP). When the outer face is bathed with a modified Ringer solution with low sodium content (2.4 mM), the transients are longer and they are only evident when the pulse is several hundred milliseconds long. With even longer pulses (several seconds) a repetitive activity can be elicited, with the electrical characteristics of a "pacemaker" activity. In all these "excitability" phenomena Na+ may be replaced by Li+ in the outer solution. The logarithm of the duration of AP's is inversely related to the logarithm of the increase in concentration of Na+ or Li+ in the solution bathing the external face of the skin. The duration of AP's is increased when the Ca++ concentration in the outer solution is raised. This effect is more evident with low sodium concentration on the outside. The evolution of the slope conductance during repetitive activity has been determined. The site and mechanisms of the "excitable" behavior of the skin and the induced repetitive activity are discussed. Under the experimental conditions employed the behavior of the skin is compared with that of normally excitable plasma membranes. PMID:5692095

Retrospective study of the clinical effects of acupuncture on cervical neurological diseases in dogs.

PubMed

Liu, Ching Ming; Chang, Fang Chia; Lin, Chung Tien

2016-09-30

This study was conducted to evaluate new acupuncture protocols for the clinical treatment of cervical spinal cord diseases in 19 dogs. Three treatment options containing Jing-jiaji (cervical jiaji) were developed to treat neck pain, hemiparesis, and tetraparesis depending on the severity. The interval between the neurological disease onset and treatment (duration of signs), time to improvement after treatment, and recovery time were compared in dogs by body weight, age, and dry needle acupuncture (AP) with or without electro-AP (EAP). The duration of signs was longer in dogs weighing greater than 10 kg than in those weighing less than 10 kg (p＜ 0.05). Improvement and recovery times did not vary by body weight. Additionally, improvement and recovery times did not vary by age. The improvement and recovery times were longer in the AP+EAP group than the AP group (p＜ 0.05). Acupuncture with Jing-jiaji was effective in cervical spinal cord diseases in different sized dogs and in middle-aged and senior dogs. This report standardized AP treatment containing Jing-jiaji for canine cervical problems and evaluated its effects. The newly standardized AP methodology offers clinical practitioners an effective way to improve the outcomes of cervical neurological diseases in dogs.

Apollo 16, LM-11 ascent propulsion system final flight evaluation

NASA Technical Reports Server (NTRS)

Griffin, W. G.

1974-01-01

The duty cycle for the LM-11 APS consisted of two firings, an ascent stage liftoff from the lunar surface, and the terminal phase initiation (TPI) burn. APS performance for the first firing was evaluated and found to be satisfactory. No propulsion data were received from the second APS burn; however, all indications were that the burn was nominal. Engine ignition for the APS lunar liftoff burn occured at the Apollo elapsed time (AET) of 175:31:47.9 (hours:minutes:seconds). Burn duration was 427.7 seconds.

Intestinal lymphangiectasia in a patient with autoimmune polyglandular syndrome type III.

PubMed

Choudhury, Bipul Kumar; Saiki, Uma Kaimal; Sarm, Dipti; Choudhury, Bikash Narayan; Choudhury, Sarojini Dutta; Saharia, Dhiren; Saikia, Mihir

2011-11-01

Autoimmune polyglandular syndromes (APS) comprise a wide clinical spectrum of autoimmune disorders. APS is divided into Type I, Type II, Type I and Type IV depending upon the pattern of disease combination. Ghronic diarrhoea is one of the many manifestations of APS and many aetiological factors have been suggested for it. Apart from the established aetiological factors, intestinal lymphangiectasia may be responsible for chronic diarrhea in some cases.Intestinal lymphangiectasia has been reported in Type I APS. We report a case of Type III APS with hypocalcaemia and hypothyroidism who had chronic diarrhea of long duration and was finally diagnosed to have intestinal lymphangiectasia.

Computational Modeling Reveals Key Contributions of KCNQ and hERG Currents to the Malleability of Uterine Action Potentials Underpinning Labor

PubMed Central

Tong, Wing-Chiu; Tribe, Rachel M.; Smith, Roger; Taggart, Michael J.

2014-01-01

The electrical excitability of uterine smooth muscle cells is a key determinant of the contraction of the organ during labor and is manifested by spontaneous, periodic action potentials (APs). Near the end of term, APs vary in shape and size reflecting an ability to change the frequency, duration and amplitude of uterine contractions. A recent mathematical model quantified several ionic features of the electrical excitability in uterine smooth muscle cells. It replicated many of the experimentally recorded uterine AP configurations but its limitations were evident when trying to simulate the long-duration bursting APs characteristic of labor. A computational parameter search suggested that delayed rectifying K+ currents could be a key model component requiring improvement to produce the longer-lasting bursting APs. Of the delayed rectifying K+ currents family it is of interest that KCNQ and hERG channels have been reported to be gestationally regulated in the uterus. These currents exhibit features similar to the broadly defined uterine I K1 of the original mathematical model. We thus formulated new quantitative descriptions for several I KCNQ and I hERG. Incorporation of these currents into the uterine cell model enabled simulations of the long-lasting bursting APs. Moreover, we used this modified model to simulate the effects of different contributions of I KCNQ and I hERG on AP form. Our findings suggest that the alterations in expression of hERG and KCNQ channels can potentially provide a mechanism for fine tuning of AP forms that lends a malleability for changing between plateau-like and long-lasting bursting-type APs as uterine cells prepare for parturition. PMID:25474527

Direct and trans-generational effects of male and female gut microbiota in Drosophila melanogaster.

PubMed

Morimoto, Juliano; Simpson, Stephen J; Ponton, Fleur

2017-07-01

There is increasing evidence of the far-reaching effects of gut bacteria on physiological and behavioural traits, yet the fitness-related consequences of changes in the gut bacteria composition of sexually interacting individuals remain unknown. To address this question, we manipulated the gut microbiota of fruit flies, Drosophila melanogaster , by monoinfecting flies with either Acetobacter pomorum ( AP ) or Lactobacillus plantarum ( LP ) . Re-inoculated individuals were paired in all treatment combinations. LP- infected males had longer mating duration and induced higher short-term offspring production in females compared with AP -infected males. Furthermore, females of either re-inoculation state mated with AP- infected males were more likely to have zero offspring after mating, suggesting a negative effect of AP on male fertility . Finally, we found that the effects of male and female gut bacteria interacted to modulate their daughters', but not sons' body mass, revealing a new trans-generational effect of parental gut microbiota. In conclusion, this study shows direct and trans-generational effects of the gut microbiota on mating and reproduction. © 2017 The Authors.

Light-Induced Translocation of RGS9-1 and Gβ5L in Mouse Rod Photoreceptors

PubMed Central

Tian, Mei; Zallocchi, Marisa; Wang, Weimin; Chen, Ching-Kang; Palczewski, Krzysztof; Delimont, Duane; Cosgrove, Dominic; Peng, You-Wei

2013-01-01

The transducin GTPase-accelerating protein complex, which determines the photoresponse duration of photoreceptors, is composed of RGS9-1, Gβ5L and R9AP. Here we report that RGS9-1 and Gβ5L change their distribution in rods during light/dark adaptation. Upon prolonged dark adaptation, RGS9-1 and Gβ5L are primarily located in rod inner segments. But very dim-light exposure quickly translocates them to the outer segments. In contrast, their anchor protein R9AP remains in the outer segment at all times. In the dark, Gβ5L's interaction with R9AP decreases significantly and RGS9-1 is phosphorylated at S475 to a significant degree. Dim light exposure leads to quick de-phosphorylation of RGS9-1. Furthermore, after prolonged dark adaptation, RGS9-1 and transducin Gα are located in different cellular compartments. These results suggest a previously unappreciated mechanism by which prolonged dark adaptation leads to increased light sensitivity in rods by dissociating RGS9-1 from R9AP and redistributing it to rod inner segments. PMID:23555598

Duration of detection of methamphetamine in hair after abstinence.

PubMed

Suwannachom, Natiprada; Thananchai, Thiwaphorn; Junkuy, Anongphan; O'Brien, Timothy E; Sribanditmongkol, Pongruk

2015-09-01

Researchers in the field of hair analysis have known for at least two decades that test results for many chemical compounds remain positive for a considerable period of time after subjects have reported cessation of use. These findings were generally based on small sample populations or individual case studies. Within the last decade, hair analyses of larger populations have investigated the phenomenon of residual positives in abstinent individuals in order to determine the period of time required for various compounds to present negative hair test results at internationally accepted cutoff levels. Such data has primarily been used to establish guidelines for retesting former abusers of illicit drugs in order to evaluate claims of abstinence. To date, research has focused on cocaine and opiates. The present study is the first to examine the duration of detection of methamphetamine (MA) and its metabolite amphetamine (AP) in the hair of chronic MA users who recently ceased their consumption of the drug. The study population (n=63) consisted of inpatients at a hospital drug rehabilitation program in Chiang Mai, Thailand. Drug taking behavior was collected by personal interview at the time of enrollment. Subjects provided hair samples at approximately monthly intervals for MA and AP analysis by gas chromatography-mass spectrometry at 0.2ng/mg cutoff levels. The correlation of baseline MA and AP concentrations in hair at the beginning of abstinence with corresponding duration of detection indicated great individual variability for the rate of clearance of MA and AP from hair. In regard to duration of detection, the majority of chronic MA users remained MA positive for up to about 90 days of reported abstinence, but by 120 days, the detection rate had fallen to about 16%. All subjects tested negative for MA after 153 days of abstinence. For AP, the limit of the duration of detection was reached at 106 days. With the adoption of a margin of safety to compensate for outlier individual variability, the present study affirmed that hair analysis of chronic MA abusers should test negative for MA after 6 months of claimed abstinence. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A KCNQ1 Mutation Causes a High Penetrance for Familial Atrial Fibrillation

PubMed Central

Bartos, Daniel C.; Anderson, Jeffrey B.; Bastiaenen, Rachel; Johnson, Jonathan N.; Gollob, Michael H; Tester, David J.; Burgess, Don E.; Homfray, Tessa; Behr, Elijah R.; Ackerman, Michael J.; Guicheney, Pascale; Delisle, Brian P.

2012-01-01

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is expected to grow. A genetic predisposition for AF has long been recognized, but its manifestation in these patients likely involves a combination of rare and common genetic variants. Identifying genetic variants that associate with a high penetrance for AF would represent a significant breakthrough for understanding the mechanisms that associate with disease. Method and Results Candidate gene sequencing in five unrelated families with familial AF identified the KCNQ1 missense mutation p.Arg231His (R231H). In addition to AF, several of the family members have abnormal QTc intervals, syncope, or experienced sudden cardiac arrest or death. KCNQ1 encodes the voltage-gated K+ channel that conducts the slowly activating delayed rectifier K+ current in the heart. Functional and computational analyses suggested that R231H increases KCNQ1 current (IKCNQ1) to shorten the atrial action potential (AP) duration. R231H is predicted to minimally affect ventricular excitability, but it prevented the increase in IKCNQ1 following PKA activation. The unique properties of R231H appeared to be caused by a loss in voltage-dependent gating. Conclusions The R231H variant causes a high penetrance for interfamilial early-onset AF. Our study indicates R231H likely shortens atrial refractoriness to promote a substrate for reentry. Additionally, R231H might cause abnormal ventricular repolarization by disrupting PKA activation of IKCNQ1. We conclude genetic variants, which increase IKs during the atrial AP, decrease the atrial AP duration, and/or shorten atrial refractoriness, present a high risk for interfamilial AF. PMID:23350853

Dendritic mechanisms underlying the coupling of the dendritic with the axonal action potential initiation zone of adult rat layer 5 pyramidal neurons

PubMed Central

Larkum, M E; Zhu, J J; Sakmann, B

2001-01-01

Double, triple and quadruple whole-cell voltage recordings were made simultaneously from different parts of the apical dendritic arbor and the soma of adult layer 5 (L5) pyramidal neurons. We investigated the membrane mechanisms that support the conduction of dendritic action potentials (APs) between the dendritic and axonal AP initiation zones and their influence on the subsequent AP pattern. The duration of the current injection to the distal dendritic initiation zone controlled the degree of coupling with the axonal initiation zone and the AP pattern. Two components of the distally evoked regenerative potential were pharmacologically distinguished: a rapidly rising peak potential that was TTX sensitive and a slowly rising plateau-like potential that was Cd2+ and Ni2+ sensitive and present only with longer-duration current injection. The amplitude of the faster forward-propagating Na+-dependent component and the amplitude of the back-propagating AP fell into two classes (more distinctly in the forward-propagating case). Current injection into the dendrite altered propagation in both directions. Somatic current injections that elicited single Na+ APs evoked bursts of Na+ APs when current was injected simultaneously into the proximal apical dendrite. The mechanism did not depend on dendritic Na+–Ca2+ APs. A three-compartment model of a L5 pyramidal neuron is proposed. It comprises the distal dendritic and axonal AP initiation zones and the proximal apical dendrite. Each compartment contributes to the initiation and to the pattern of AP discharge in a distinct manner. Input to the three main dendritic arbors (tuft dendrites, apical oblique dendrites and basal dendrites) has a dominant influence on only one of these compartments. Thus, the AP pattern of L5 pyramids reflects the laminar distribution of synaptic activity in a cortical column. PMID:11389204

IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

PubMed Central

Vaidyanathan, Ravi; Markandeya, Yogananda S.; Kamp, Timothy J.; Makielski, Jonathan C.; January, Craig T.

2016-01-01

Currently available induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) do not ideally model cellular mechanisms of human arrhythmic disease due to lack of a mature action potential (AP) phenotype. In this study, we create and characterize iPS-CMs with an electrically mature AP induced by potassium inward rectifier (IK1) enhancement. The advantages of IK1-enhanced iPS-CMs include the absence of spontaneous beating, stable resting membrane potentials at approximately −80 mV and capability for electrical pacing. Compared with unenhanced, IK1-enhanced iPS-CMs calcium transient amplitudes were larger (P < 0.05) with a typical staircase pattern. IK1-enhanced iPS-CMs demonstrated a twofold increase in cell size and membrane capacitance and increased DNA synthesis compared with control iPS-CMs (P < 0.05). Furthermore, IK1-enhanced iPS-CMs expressing the F97C-CAV3 long QT9 mutation compared with wild-type CAV3 demonstrated an increase in AP duration and late sodium current. IK1-enhanced iPS-CMs represent a more mature cardiomyocyte model to study arrhythmia mechanisms. PMID:27059077

Increased treatment durations lead to greater improvements in non-weight bearing dorsiflexion range of motion for asymptomatic individuals immediately following an anteroposterior grade IV mobilisation of the talus.

PubMed

Holland, Christopher James; Campbell, Kevin; Hutt, Kim

2015-08-01

Manual therapy aims to minimise pain and restore joint mobility and function. Joint mobilisations are integral to these techniques, with anteroposterior (AP) talocrural joint mobilisations purported to increase dorsiflexion range of motion (DF-ROM). This study aimed to determine whether different treatment durations of single grade IV anteroposterior talocrural joint mobilisations elicit statistically significant differences in DF-ROM. Sixteen asymptomatic male football players (age = 27.1 ± 5.3 years) participated in the study. Non-weight bearing (NWB) and weight bearing (WB) DF-ROM was measured before and after 4 randomised treatment conditions: control treatment, 30 s, 1 min, 2 min. NWB DF-ROM was measured using a universal goniometer, and WB DF-ROM using the weight-bearing lunge test. A within-subjects design was employed so that all participants received each of the treatment conditions. A 4 × 4 balanced Latin square design and 1 week interval between sessions reduced any residual effects. Two-way repeated measures ANOVA revealed a significant improvement in DF-ROM following all AP mobilisation treatments (p < 0.001). The within subjects contrasts showed that increases in treatment duration was associated with statistically significant improvements in DF-ROM (NWB DF-ROM control = 0.01%, 30 s = 14.2%, 1 min = 21.6%, 2 min = 32.8%; WB DF-ROM control = 0.01%, 30 s = 5.0%, 1 min = 7.6%, 2 min = 10.9%; p < 0.05). However, WB DF-ROM improvements were below the minimal detectable change scores needed to conclude that improvements were not a consequence of measurement error. This research shows that single session mobilisations can elicit NWB DF-ROM improvements in asymptomatic individuals in the absence of pain, whilst increases in treatment duration confer greater improvements in NWB DF-ROM within this population. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparative sonographic evaluation of the anteroposterior dimensions of the pancreas in diabetics and nondiabetics.

PubMed

Agabi, J O; Akhigbe, A O

2016-01-01

The pancreas is an insulin-producing gland and is prone to varying degrees of destruction and change in patients with diabetes mellitus (DM). Various morphological changes including reduction in the pancreas dimensions have been described in DM. To determine pancreatic anteroposterior (AP) dimensions in diabetics by sonography and compare with nondiabetics. To also evaluate the correlation of the AP dimensions with patient's anthropometry, as well as the duration of the disease in comparison with nondiabetics. This is a comparative cross-sectional study involving 150 diabetics with 150 sex and age matched healthy normoglycemic group used as controls. Sonographic measurements of the AP dimensions of the pancreatic head, body, and tail of both study groups were performed with the use of 3.5 MHz curvilinear array transducer of a SonoAce X4 ultrasound machine. Data were analyzed using Statistical Package for Social Sciences version 17 (SPSS Inc., Chicago, IL, USA). A statistical test was considered significant at P ≤ 0.05 and 95% confidence interval. Pancreas AP dimensions were significantly smaller in diabetics compared to those of the controls. The mean dimensions were 1.91 ± 0.26 cm, 0.95 ± 0.12 cm, and 0.91 ± 0.11 cm for the head, body, and tail, respectively, in diabetics and 2.32 ± 0.22 cm, 1.43 ± 0.19 cm, and 1.34 ± 0.20 cm in the control (P < 0.001 in all cases). The dimensions were also significantly smaller in the Type 1 diabetics compared to Type 2 (P < 0.001 in all cases). The mean duration of illness for the Types 1 and 2 diabetics were 3.09 ± 1.38 and 3.78 ± 3.12 years, respectively. Longer duration of illness was associated with smaller pancreas body and tail dimensions, while pancreas head dimension was not significantly affected by the duration of illness. Diabetics have smaller pancreas AP dimensions compared to the normal population.

A Simple Postflight Measure of Postural Atania in Astronauts

NASA Technical Reports Server (NTRS)

Reschke, M. F.; Harm, D. I.; Kofman, I. S.; Wood, S. J.; Bloomberg, J. J.

2011-01-01

Astronauts returning from space flight universally present with postural ataxia. Throughout the Space Shuttle Program, measurement of ataxia has concentrated on sway in the anterior-posterior (AP) plane. The current investigation, as a part of a larger functional study, concentrated on characterizing postural instability using dynamic stabilographic sway patterns in both the AP and medial-lateral (ML) planes. To accomplish this goal, six astronauts from short-duration (Shuttle) and three from long-duration (ISS) flights were required to recover from a simulated fall. Subjects with eyes open, wearing running shoes lay prone on the floor for 2 minutes and then quickly stood up, maintained a quiet stance for 3 minutes, arms relaxed along the side of the body, and feet comfortably placed on the force plate. Crewmembers were tested twice before flight, on landing day (Shuttle only), and 1, 6, and 30 days after flight. Anterior-posterior and ML center-of-pressure (COP) coordinates were calculated from the ground reaction forces collected at 500 Hz. The 3-minute quiet stance trial was broken into three 1-minute segments for stabilogram diffusion analysis. A mean sway speed (rate of change of COP displacement) was also calculated as an additional postural stability parameter. While there was considerable variation, most of crewmembers tested exhibited increased stochastic activity evidenced by larger short-term COP diffusion coefficients postflight in both the AP and ML planes, suggesting significant changes in postural control mechanisms, particularly control of lower limb muscle function. As expected, postural instability of ISS astronauts on the first day postflight was similar to that of Shuttle crewmembers on landing day. Recoveries of stochastic activity and mean sway speed to baseline levels were typically observed by the 30th day postflight for both long-duration and short-duration crewmembers. Dynamic postural stability characteristics obtained in this low-impact study complement the data measured with computerized dynamic posturography.

The actions of mdivi-1, an inhibitor of mitochondrial fission, on rapidly activating delayed-rectifier K⁺ current and membrane potential in HL-1 murine atrial cardiomyocytes.

PubMed

So, Edmund Cheung; Hsing, Chung-Hsi; Liang, Chia-Hua; Wu, Sheng-Nan

2012-05-15

Mdivi-1 is an inhibitor of dynamin related protein 1- (drp1)-mediated mitochondrial fission. However, the mechanisms through which this compound interacts directly with ion currents in heart cells remain unknown. In this study, its effects on ion currents and membrane potential in murine HL-1 cardiomyocytes were investigated. In whole-cell recordings, the addition of mdivi-1 decreased the amplitude of tail current (I(tail)) for the rapidly activating delayed-rectifier K⁺ current (I(Kr)) in a concentration-dependent manner with an IC₅₀ value at 11.6 μM, a value that resembles the inhibition requirement for mitochondrial division. It shifted the activation curve of I(tail) to depolarized voltages with no change in the gating charge. However, mdivi-1 did not alter the rate of recovery from current inactivation. In cell-attached configuration, mdivi-1 inside the pipette suppressed the activity of acetylcholine-activated K⁺ channels without modifying the single-channel conductance. Mdivi-1 (30 μM) slightly depressed the peak amplitude of Na⁺ current with no change in the overall current-voltage relationship. Under current-clamp recordings, addition of mdivi-1 resulted in prolongation for the duration of action potentials (APs) and to increase the firing of spontaneous APs in HL-1 cells. Similarly, in pituitary GH₃ cells, mdivi-1 was effective in directly suppressing the amplitude of ether-à-go-go-related gene-mediated K⁺ current. Therefore, the lengthening of AP duration and increased firing of APs caused by mdivi-1 can be primarily explained by its inhibition of these K⁺ channels enriched in heart cells. The observed effects of mdivi-1 on ion currents were direct and not associated with its inhibition of mitochondrial division. Copyright © 2012 Elsevier B.V. All rights reserved.

Private sector participation in delivering tertiary health care: a dichotomy of access and affordability across two Indian states.

PubMed

Katyal, Anuradha; Singh, Prabal Vikram; Bergkvist, Sofi; Samarth, Amit; Rao, Mala

2015-03-01

Poor quality care in public sector hospitals coupled with the costs of care in the private sector have trapped India's poor in a vicious cycle of poverty, ill health and debt for many decades. To address this, the governments of Andhra Pradesh (AP) and Maharashtra (MH), India, have attempted to improve people's access to hospital care by partnering with the private sector. A number of government-sponsored schemes with differing specifications have been launched to facilitate this strategy. This article aims to compare changes in access to, and affordability and efficiency of private and public hospital inpatient (IP) treatments between MH and AP from 2004 to 2012 and to assess whether the health financing innovations in one state resulted in larger or smaller benefits compared with the other. We used data from household surveys conducted in 2004 and 2012 in the two states and undertook a difference-in-difference (DID) analysis. The results focus on hospitalization, out-of-pocket expenditure and length of stay. The average IP expenditure for private hospital care has increased in both states, but more so in MH. There was also an observable increase in both utilization of and expenditure on nephrology treatment in private hospitals in AP. The duration of stay recorded in days for private hospitals has increased slightly in MH and declined in AP with a significant DID. The utilization of public hospitals has reduced in AP and increased in MH. The state of AP appears to have benefited more than MH in terms of improved access to care by involving the private sector. The Aarogyasri scheme is likely to have contributed to these impacts in AP at least in part. Our study needs to be followed up with repeated evaluations to ascertain the long-term impacts of involving the private sector in providing hospital care. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine © The Author 2015; all rights reserved.

Postural control strategies related to anticipatory perturbation and quick perturbation in adolescent idiopathic scoliosis.

PubMed

Kuo, Fang-Chuan; Hong, Chang-Zern; Lai, Chung-Liang; Tan, Shih-Hsin

2011-05-01

Cross-sectional study. To investigate the automatic balance correction related to anticipatory perturbation (AP) and quick backward perturbation in adolescent idiopathic scoliosis (AIS). Most previous studies on AIS patients focused on posture sway and lacked analysis of muscle activated patterns in dynamic standing control. Thirty-two AIS patients and 23 age-matched normal subjects received perturbation balance tests on an unstable platform. The tilting angle of the platform and the muscle activity of the bilateral lumbar multifidi, gluteus medii, and gastrocnemii muscles were recorded. Electromyographic (EMG) amplitude, onset latencies, and duration were calculated with software accompanied with machine. The AIS group had less posture tilting but higher muscle activities than normal subjects under both perturbation conditions (P < 0.05). Under the AP test, AIS showed earlier onset and prolonged activation of left multifidus and right gastrocnemius compared with normal subjects (P < 0.05). The latency of the multifidus on the lumbar convex side occurred earlier than on the concave side. However, the asymmetric onset timing of the gastrocnemius was the opposite of the multifidi in the AIS group (P < 0.05). In contrast to the AP condition, bilateral leg and trunk muscles activated at similar latencies and durations in the AIS group (P < 0.05). Under the quick backward perturbation test, the control group had longer active duration of right multifidus and bilateral gastrocnemii than AIS to cope with larger platform tilting. In addition, asymmetric onset of gluteus medii and duration of multifidi was observed in the control group (P < 0.05). There were significant differences in posture control patterns between AIS and normal subjects. AIS subjects have asymmetric habitual muscle activities for AP, whereas when coping with sudden balance threats, they react with synchronized recruitment of bilateral postural muscles.

Modulation of ventricular transient outward K+ current by acidosis and its effects on excitation-contraction coupling

PubMed Central

Saegusa, Noriko; Garg, Vivek

2013-01-01

The contribution of transient outward current (Ito) to changes in ventricular action potential (AP) repolarization induced by acidosis is unresolved, as is the indirect effect of these changes on calcium handling. To address this issue we measured intracellular pH (pHi), Ito, L-type calcium current (ICa,L), and calcium transients (CaTs) in rabbit ventricular myocytes. Intracellular acidosis [pHi 6.75 with extracellular pH (pHo) 7.4] reduced Ito by ∼50% in myocytes with both high (epicardial) and low (papillary muscle) Ito densities, with little effect on steady-state inactivation and activation. Of the two candidate α-subunits underlying Ito, human (h)Kv4.3 and hKv1.4, only hKv4.3 current was reduced by intracellular acidosis. Extracellular acidosis (pHo 6.5) shifted Ito inactivation toward less negative potentials but had negligible effect on peak current at +60 mV when initiated from −80 mV. The effects of low pHi-induced inhibition of Ito on AP repolarization were much greater in epicardial than papillary muscle myocytes and included slowing of phase 1, attenuation of the notch, and elevation of the plateau. Low pHi increased AP duration in both cell types, with the greatest lengthening occurring in epicardial myocytes. The changes in epicardial AP repolarization induced by intracellular acidosis reduced peak ICa,L, increased net calcium influx via ICa,L, and increased CaT amplitude. In summary, in contrast to low pHo, intracellular acidosis has a marked inhibitory effect on ventricular Ito, perhaps mediated by Kv4.3. By altering the trajectory of the AP repolarization, low pHi has a significant indirect effect on calcium handling, especially evident in epicardial cells. PMID:23585132

Interaction of sleep quality and sleep duration on impaired fasting glucose: a population-based cross-sectional survey in China.

PubMed

Lou, Peian; Chen, Peipei; Zhang, Lei; Zhang, Pan; Chang, Guiqiu; Zhang, Ning; Li, Ting; Qiao, Cheng

2014-03-13

To explore the interactions of sleep quality and sleep duration and their effects on impaired fasting glucose (IFG) in Chinese adults. Cross-sectional survey. Community-based investigation in Xuzhou, China. 15 145 Chinese men and women aged 18-75 years old who fulfilled the inclusion criteria. The Pittsburgh Sleep Quality Index was used to produce sleep quality categories of good, common and poor. Fasting blood glucose levels were assessed for IFG. Sleep duration was measured by average hours of sleep per night, with categories of <6, 6-8 and >8 h. The products of sleep and family history of diabetes, obesity and age were added to the logistic regression model to evaluate the addictive interaction and relative excess risk of interaction (RERI) on IFG. The attributable proportion (AP) of the interaction and the synergy index (S) were applied to evaluate the additive interaction of two factors. Bootstrap measures were used to calculate 95% CI of RERI, AP and S. The prevalence of IFG was greatest in those with poor sleep quality and short sleep duration (OR 6.37, 95% CI 4.66 to 8.67; p<0.001) compared with those who had good sleep quality and 6-8 h sleep duration, after adjusting for confounders. After adjusting for potential confounders RERI, AP and S values (and their 95% CI) were 1.69 (0.31 to 3.76), 0.42 (0.15 to 0.61) and 2.85 (2.14 to 3.92), respectively, for the interaction between poor sleep quality and short sleep duration, and 0.78 (0.12 to 1.43), 0.61 (0.26 to 0.87) and -65 (-0.94 to -0.27) for the interaction between good sleep quality and long sleep duration. The results suggest that there are additive interactions between poor sleep quality and short sleep duration.

Easy Method to Examine Single Nerve Fiber Excitability and Conduction Parameters Using Intact Nonanesthetized Earthworms

ERIC Educational Resources Information Center

Bähring, Robert; Bauer, Christiane K.

2014-01-01

The generation and conduction of neuronal action potentials (APs) were the subjects of a cell physiology exercise for first-year medical students. In this activity, students demonstrated the all-or-none nature of AP generation, measured conduction velocity, and examined the dependence of the threshold stimulus amplitude on stimulus duration. For…

Microstructures and Hardness of the High Chromium Oxide Dispersion Strengthened Alloy Fe-25Cr-Y2O3Sintered by the Arc Plasma Sintering (APS)

NASA Astrophysics Data System (ADS)

Bandriyana; Dimyati, Arbi; Sujatno, Agus; Salam, Rohmad; Sumaryo; Untoro, Pudji; Suharno, Bambang

2018-03-01

High chromium ODS alloy has been developed for application as structural material in high temperature nuclear reactor. In the present study, Fe-25Cr-Y2O3 with dispersed 0.5 wt.% Ytria (Y2O3) were synthesized and characterized by means of various techniques as a function of milling time 1, 2 and 3 hours. The alloy synthesis was carried out by the Mechanical Alloying (MA) process and subsequent sintering by means the new plasma technique using the APS apparatus. Scaning Electron Microscopy (SEM) and X-ray diffraction (XRD) were conducted for morphology and phase analysis. Evaluation of the mechanical properties was studied based on the Vickers hardness measurement. SEM examination revealed that the sample after sintering by APS method at different milling duration exhibited some particle aglomeration and homogenized oxide dispersion that obviously strengthened the alloy. The XRD test, however, proved the formation of the main phase Fe-Cr. The alloy showed exceptionally high hardness of 193 VHR which is mainly due to the grain refining that increase by the increasing of the milling time.

Systolic blood pressure but not electrocardiogram QRS duration is associated with heart rate variability (HRV): a cross-sectional study in rural Australian non-diabetics.

PubMed

Lee, Yvonne Yin Leng; Jelinek, Herbert F; McLachlan, Craig S

2017-01-01

A positive correlation between ECG derived QRS duration and heart rate variability (HRV) parameters had previously been reported in young healthy adults. We note this study used a narrow QRS duration range, and did not adjust for systolic blood pressure. Our aims are to investigate associations between systolic blood pressure (SBP), QRS duration and HRV in a rural aging population. A retrospective cross sectional population was obtained from the CSU Diabetes Screening Research Initiative data base where 200 participants had no diabetes or pre-diabetes. SBP data were matched with ECG derived QRS duration and HRV parameters. HRV parameters were calculated from R-R intervals. Resting 12-lead electrocardiograms were obtained from each subject using a Welch Allyn PC-Based ECG system. Pearson correlation analysis revealed no statistically significant associations between HRV parameters and QRS duration. No significant mean differences in HRV parameter subgroups across defined QRS cut-offs were found. SBP > 146 mmHg was associated with increasing QRS durations, however this association disappeared once models were adjusted for age and gender. SBP was also significantly associated with a number of HRV parameters using Pearson correlation analysis, including high frequency (HF) ( p  < 0.05), HFln ( p  < 0.02), RMSDD ( p  < 0.02) and non-linear parameters; ApEN ( p  < 0.001) were negatively correlated with increasing SBP while the low frequency to high frequency ratio (LF/HF) increased with increasing SBP ( p  < 0.03). Our results do not support associations between ECG derived R-R derived HRV parameters and QRS duration in aging populations. We suggest that ventricular conduction as determined by QRS duration is independent of variations in SA-node heart rate variability.

ParamAP: Standardized Parameterization of Sinoatrial Node Myocyte Action Potentials.

PubMed

Rickert, Christian; Proenza, Catherine

2017-08-22

Sinoatrial node myocytes act as cardiac pacemaker cells by generating spontaneous action potentials (APs). Much information is encoded in sinoatrial AP waveforms, but both the analysis and the comparison of AP parameters between studies is hindered by the lack of standardized parameter definitions and the absence of automated analysis tools. Here we introduce ParamAP, a standalone cross-platform computational tool that uses a template-free detection algorithm to automatically identify and parameterize APs from text input files. ParamAP employs a graphic user interface with automatic and user-customizable input modes, and it outputs data files in text and PDF formats. ParamAP returns a total of 16 AP waveform parameters including time intervals such as the AP duration, membrane potentials such as the maximum diastolic potential, and rates of change of the membrane potential such as the diastolic depolarization rate. ParamAP provides a robust AP detection algorithm in combination with a standardized AP parameter analysis over a wide range of AP waveforms and firing rates, owing in part to the use of an iterative algorithm for the determination of the threshold potential and the diastolic depolarization rate that is independent of the maximum upstroke velocity, a parameter that can vary significantly among sinoatrial APs. Because ParamAP is implemented in Python 3, it is also highly customizable and extensible. In conclusion, ParamAP is a powerful computational tool that facilitates quantitative analysis and enables comparison of sinoatrial APs by standardizing parameter definitions and providing an automated work flow. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Relationship between antipsychotics and weight in patients with Prader-Willi syndrome.

PubMed

Elliott, Jennifer Padden; Cherpes, Gregory; Kamal, Khalid; Chopra, Ishveen; Harrison, Chelsea; Riedy, Mary; Herk, Brandon; McCrossin, Matt; Kalarchian, Melissa

2015-03-01

Individuals with Prader-Willi Syndrome (PWS) are at increased risk for developing behavioral and psychiatric disorders, often requiring antipsychotics (APs). Contrary to significant AP-associated weight gain observed in the general population, existing literature suggests weight loss in patients with PWS. To evaluate the relationship between AP use and body mass index (BMI) at admission, change in BMI during inpatient stay, and length of stay (LOS) in patients admitted to an inpatient PWS treatment program. Retrospective case-control study. Hospital-based, inpatient PWS treatment program serving nationally and internationally referred children and adults with PWS. Cases consisted of 52 pediatric patients with PWS who were taking APs at admission and during their stay, 97 adults with PWS who were taking APs at admission and during their stay, and 11 pediatric and adult patients with PWS who were AP naïve at admission and subsequently started an AP during their stay; all cases were matched with patients with PWS who were AP naïve at admission and during their stay by age (yrs), sex, and race-ethnicity (controls). Between- and within-group differences in admission BMI, BMI change from admission to discharge, and LOS were analyzed. Admission BMI was lower (mean ± SD 36.8 ± 11.9 kg/m(2) vs 46.7 ± 12.5 kg/m(2) , p<0.001) and LOS longer (mean ± SD 75.9 ± 38.5 days vs 57.8 ± 23.2 days, p=0.005) for pediatric cases with AP exposure at admission and during their stay compared with matched controls. All groups experienced significant decreases in BMI from admission to discharge (p≤0.001 for all comparisons), except for pediatric cases with AP exposure at admission and during their stay. Cases that were AP naïve at admission and subsequently started an AP during their inpatient stay experienced a significantly smaller decrease in BMI from admission to discharge than matched controls (-3.011 vs -7.288 kg/m(2) , p=0.027). No other comparisons between cases and controls were significantly different. On average, patients with PWS who were prescribed APs lost weight during their inpatient stay, but this varied with patient age and duration of AP use. © 2015 Pharmacotherapy Publications, Inc.

Transmural ultrasound imaging of thermal lesion and action potential changes in perfused canine cardiac wedge preparations by high intensity focused ultrasound ablation.

PubMed

Wu, Ziqi; Gudur, Madhu S R; Deng, Cheri X

2013-01-01

Intra-procedural imaging is important for guiding cardiac arrhythmia ablation. It is difficult to obtain intra-procedural correlation of thermal lesion formation with action potential (AP) changes in the transmural plane during ablation. This study tested parametric ultrasound imaging for transmural imaging of lesion and AP changes in high intensity focused ultrasound (HIFU) ablation using coronary perfused canine ventricular wedge preparations (n = 13). The preparations were paced from epi/endocardial surfaces and subjected to HIFU application (3.5 MHz, 11 Hz pulse-repetition-frequency, 70% duty cycle, duration 4 s, 3500 W/cm(2)), during which simultaneous optical mapping (1 kframes/s) using di-4-ANEPPS and ultrasound imaging (30 MHz) of the same transmural surface of the wedge were performed. Spatiotemporally correlated AP measurements and ultrasound imaging allowed quantification of the reduction of AP amplitude (APA), shortening of AP duration at 50% repolarization, AP triangulation, decrease of optical AP rise, and change of conduction velocity along tissue depth direction within and surrounding HIFU lesions. The threshold of irreversible change in APA correlating to lesions was determined to be 43 ± 1% with a receiver operating characteristic (ROC) area under curve (AUC) of 0.96 ± 0.01 (n = 13). Ultrasound imaging parameters such as integrated backscatter, Rayleigh (α) and log-normal (σ) parameters, cumulative extrema of σ were tested, with the cumulative extrema of σ performing the best in detecting lesion (ROC AUC 0.89 ± 0.01, n = 13) and change of APA (ROC AUC 0.79 ± 0.03, n = 13). In conclusion, characteristic tissue and AP changes in HIFU ablation were identified and spatiotemporally correlated using optical mapping and ultrasound imaging. Parametric ultrasound imaging using cumulative extrema of σ can detect HIFU lesion and APA reduction.

Transmural Ultrasound Imaging of Thermal Lesion and Action Potential Changes in Perfused Canine Cardiac Wedge Preparations by High Intensity Focused Ultrasound Ablation

PubMed Central

Wu, Ziqi; Gudur, Madhu S. R.; Deng, Cheri X.

2013-01-01

Intra-procedural imaging is important for guiding cardiac arrhythmia ablation. It is difficult to obtain intra-procedural correlation of thermal lesion formation with action potential (AP) changes in the transmural plane during ablation. This study tested parametric ultrasound imaging for transmural imaging of lesion and AP changes in high intensity focused ultrasound (HIFU) ablation using coronary perfused canine ventricular wedge preparations (n = 13). The preparations were paced from epi/endocardial surfaces and subjected to HIFU application (3.5 MHz, 11 Hz pulse-repetition-frequency, 70% duty cycle, duration 4 s, 3500 W/cm2), during which simultaneous optical mapping (1 kframes/s) using di-4-ANEPPS and ultrasound imaging (30 MHz) of the same transmural surface of the wedge were performed. Spatiotemporally correlated AP measurements and ultrasound imaging allowed quantification of the reduction of AP amplitude (APA), shortening of AP duration at 50% repolarization, AP triangulation, decrease of optical AP rise, and change of conduction velocity along tissue depth direction within and surrounding HIFU lesions. The threshold of irreversible change in APA correlating to lesions was determined to be 43±1% with a receiver operating characteristic (ROC) area under curve (AUC) of 0.96±0.01 (n = 13). Ultrasound imaging parameters such as integrated backscatter, Rayleigh (α) and log-normal (σ) parameters, cumulative extrema of σ were tested, with the cumulative extrema of σ performing the best in detecting lesion (ROC AUC 0.89±0.01, n = 13) and change of APA (ROC AUC 0.79±0.03, n = 13). In conclusion, characteristic tissue and AP changes in HIFU ablation were identified and spatiotemporally correlated using optical mapping and ultrasound imaging. Parametric ultrasound imaging using cumulative extrema of σ can detect HIFU lesion and APA reduction. PMID:24349337

A mathematical model of action potential heterogeneity in adult rat left ventricular myocytes.

PubMed Central

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

Interaction of sleep quality and sleep duration on impaired fasting glucose: a population-based cross-sectional survey in China

PubMed Central

Lou, Peian; Chen, Peipei; Zhang, Lei; Zhang, Pan; Chang, Guiqiu; Zhang, Ning; Li, Ting; Qiao, Cheng

2014-01-01

Objectives To explore the interactions of sleep quality and sleep duration and their effects on impaired fasting glucose (IFG) in Chinese adults. Design Cross-sectional survey. Setting Community-based investigation in Xuzhou, China. Participants 15 145 Chinese men and women aged 18–75 years old who fulfilled the inclusion criteria. Primary and secondary outcome measures The Pittsburgh Sleep Quality Index was used to produce sleep quality categories of good, common and poor. Fasting blood glucose levels were assessed for IFG. Sleep duration was measured by average hours of sleep per night, with categories of <6, 6–8 and >8 h. The products of sleep and family history of diabetes, obesity and age were added to the logistic regression model to evaluate the addictive interaction and relative excess risk of interaction (RERI) on IFG. The attributable proportion (AP) of the interaction and the synergy index (S) were applied to evaluate the additive interaction of two factors. Bootstrap measures were used to calculate 95% CI of RERI, AP and S. Results The prevalence of IFG was greatest in those with poor sleep quality and short sleep duration (OR 6.37, 95% CI 4.66 to 8.67; p<0.001) compared with those who had good sleep quality and 6–8 h sleep duration, after adjusting for confounders. After adjusting for potential confounders RERI, AP and S values (and their 95% CI) were 1.69 (0.31 to 3.76), 0.42 (0.15 to 0.61) and 2.85 (2.14 to 3.92), respectively, for the interaction between poor sleep quality and short sleep duration, and 0.78 (0.12 to 1.43), 0.61 (0.26 to 0.87) and −65 (−0.94 to −0.27) for the interaction between good sleep quality and long sleep duration. Conclusions The results suggest that there are additive interactions between poor sleep quality and short sleep duration. PMID:24625639

Diadenosine tetra- and pentaphosphates affect contractility and bioelectrical activity in the rat heart via P2 purinergic receptors.

PubMed

Pustovit, Ksenia B; Kuzmin, Vladislav S; Abramochkin, Denis V

2016-03-01

Diadenosine polyphosphates (Ap(n)As) are endogenously produced molecules which have been identified in various tissues of mammalian organism, including myocardium. Ap(n)As contribute to the blood clotting and are also widely accepted as regulators of blood vascular tone. Physiological role of Ap(n)As in cardiac muscle has not been completely elucidated. The present study aimed to investigate the effects of diadenosine tetra- (Ap4A) and penta- (Ap5A) polyphosphates on contractile function and action potential (AP) waveform in rat supraventricular and ventricular myocardium. We have also demonstrated the effects of A4pA and Ap5A in myocardial sleeves of pulmonary veins (PVs), which play a crucial role in genesis of atrial fibrillation. APs were recorded with glass microelectrodes in multicellular myocardial preparations. Contractile activity was measured in isolated Langendorff-perfused rat hearts. Both Ap4A and Ap5A significantly reduced contractility of isolated Langendorff-perfused heart and produced significant reduction of AP duration in left and right auricle, interatrial septum, and especially in right ventricular wall myocardium. Ap(n)As also shortened APs in rat pulmonary veins and therefore may be considered as potential proarrhythmic factors. Cardiotropic effects of Ap4A and Ap5A were strongly antagonized by selective blockers of P2 purine receptors suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), while P1 blocker DPCPX was not effective. We conclude that Ap(n)As may be considered as new class of endogenous cardioinhibitory compounds. P2 purine receptors play the central role in mediation of Ap4A and Ap5A inhibitory effects on electrical and contractile activity in different regions of the rat heart.

Measuring Transcutaneous Oxygenation to Validate the Duration Required to Achieve Electrode Equilibration.

PubMed

Chiang, Nathaniel; Jain, Jitendra K; Sleigh, Jamie; Vasudevan, Thodur

2018-06-01

The transcutaneous oxygenation measurement (TCOM) system is useful in assessing tissue viability. There are no clear recommendations regarding the duration required for the electrode to equilibrate and reliably evaluate tissue oxygenation values. The objective of this study was to validate the duration required to achieve electrode equilibration in a clinical setting. Minute-by-minute recordings using TCOM (TCOM3; Radiometer Medical ApS, Brønshøj, Copenhagen) were obtained for 82 limbs in 50 participants. Twenty-five limbs were in patients with peripheral vascular disease; 30 were in patients with no known peripheral vascular disease; and 27 were in healthy volunteers. Transcutaneous partial pressure of oxygen and carbon dioxide (TcPO2 and TcPCO2) were recorded over a 15-minute period. Participants' TcPO2 decreased and TcPCO2 increased over time. Both changed in a nonlinear fashion, eventually settling at an "equilibrium" where the measurements became stable. The difference in proportional change of TcPO2 between minutes 14 and 15 was 0.8%, and for TcPCO2was 2.9%. Changes in TCOM measurements over time were similar among the 3 groups. This is the first study to target minute-by-minute variation in TcPO2 and TcPCO2 measurements. Recording for a minimum of 15 minutes allows a reliable period for the TCOM electrode to equilibrate to record absolute values and determine wound healing potential.

Prevalence of increased canine pancreas-specific lipase concentrations in young dogs with parvovirus enteritis.

PubMed

Kalli, Irida V; Adamama-Moraitou, Katerina K; Patsika, Michael N; Pardali, Dimitra; Steiner, Jörg M; Suchodolski, Jan S; Menexes, George; Brellou, Georgia D; Rallis, Timoleon S

2017-03-01

Pancreatic abnormalities during canine parvovirus (CPV) enteritis have not been studied prospectively. The objective of this study was to evaluate the diagnostic significance of canine serum pancreas-specific lipase (Spec cPL) concentration in dogs with CPV enteritis for the presence of acute pancreatitis (AP). Puppies with naturally occurring CPV enteritis were recruited and prospectively allocated into 2 groups according to normal or increased serum Spec cPL concentration. Clinical signs, laboratory findings, and pancreas-associated variables were compared between groups, and the impact of possible AP on disease course, duration of hospitalization, and outcome was assessed. Serum Spec cPL concentration in 35 puppies was above the upper limit of the RI in 17/35 (48.6%) dogs (Group A) and within the RI in 18 dogs (Group B). An increased serum lipase activity was present in 29/35 (82.9%) dogs, and Group A dogs had a higher serum lipase activity than Group B (P = .006). Serum Spec cPL in Group A dogs was positively correlated with serum lipase activity at the day of presentation (r = .667; P = .003) and day of discharge (r = .628; P = .007). No statistically significant difference was found between groups (P = .233) for the presence of systemic inflammatory response syndrome (SIRS) (6/17 or 35.3% dogs Group A, and 8/18 or 44.4% dogs Group B), the disease course, duration of hospitalization, or outcome between groups. Increased serum Spec cPL is relatively common in dogs with CPV enteritis. However, such increases do not seem to correlate with the outcome of disease. © 2017 American Society for Veterinary Clinical Pathology.

An examination of two emergency breathing aids for use during helicopter underwater escape.

PubMed

Tipton, M J; Franks, C M; Sage, B A; Redman, P J

1997-10-01

There is a paucity of published work in which the performance of Emergency Underwater Breathing Aids (EUBA) has been examined in the wide range of scenarios in which helicopter underwater escape may be necessary. In the present investigation two EUBA were examined: the Air Pocket (AP) rebreather and the Short Term Air Supply System (STASS) mini SCUBA set. Young, healthy male subjects undertook simple simulated helicopter underwater escapes in water at 15 degrees C and/or 5 degrees C. During the immersions the subjects attempted to remain submerged for 60 s while traversing back and forth along a ladder secured at a depth of 1.25 m. At each temperature the subjects used AP and STASS twice. The subjects were dressed in the Royal Navy winter sea helicopter aircrew equipment assembly and an aircrew helmet. Both AP and STASS significantly extended the underwater survival time of individuals when compared to their maximum breath-hold time (BHT). It is clear from the measurements made of gas concentrations in AP; the volume of air used from STASS; and subjective responses, that the 60-s submersions were achieved more easily with STASS than AP. It is concluded that in conditions similar to those of the present experiment STASS will give a longer underwater duration than AP, but this benefit must be offset against the possible risk of pulmonary barotrauma associated with the use of STASS, as well as increased training and maintenance costs. Irrespective of the EUBA which is provided, in-water training, preferably including exposure to cold water, will significantly improve the ability of an individual to use it.

Role of Cerebellum in Motion Perception and Vestibulo-ocular Reflex—Similarities and Disparities

PubMed Central

Shaikh, Aasef G.; Palla, Antonella; Marti, Sarah; Olasagasti, Itsaso; Optican, Lance M.; Zee, David S.; Straumann, Dominik

2012-01-01

Vestibular velocity storage enhances the efficacy of the angular vestibulo-ocular reflex (VOR) during relatively low-frequency head rotations. This function is modulated by GABA-mediated inhibitory cerebellar projections. Velocity storage also exists in perceptual pathway and has similar functional principles as VOR. However, it is not known whether the neural substrate for perception and VOR overlap. We propose two possibilities. First, there is the same velocity storage for both VOR and perception; second, there are nonoverlapping neural networks: one might be involved in perception and the other for the VOR. We investigated these possibilities by measuring VOR and perceptual responses in healthy human subjects during whole-body, constant-velocity rotation steps about all three dimensions (yaw, pitch, and roll) before and after 10 mg of 4-aminopyridine (4-AP). 4-AP, a selective blocker of inward rectifier potassium conductance, can lead to increased synchronization and precision of Purkinje neuron discharge and possibly enhance the GABAergic action. Hence 4-AP could reduce the decay time constant of the perceived angular velocity and VOR. We found that 4-AP reduced the decay time constant, but the amount of reduction in the two processes, perception and VOR, was not the same, suggesting the possibility of nonoverlapping or partially overlapping neural substrates for VOR and perception. We also noted that, unlike the VOR, the perceived angular velocity gradually built up and plateau prior to decay. Hence, the perception pathway may have additional mechanism that changes the dynamics of perceived angular velocity beyond the velocity storage. 4-AP had no effects on the duration of build-up of perceived angular velocity, suggesting that the higher order processing of perception, beyond the velocity storage, might not occur under the influence of mechanism that could be influenced by 4-AP. PMID:22777507

Pro‐arrhythmic atrial phenotypes in incrementally paced murine Pgc1β −/− hearts: effects of age

PubMed Central

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

Cardiac tissue slices: preparation, handling, and successful optical mapping.

PubMed

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.

Cardiac tissue slices: preparation, handling, and successful optical mapping

PubMed Central

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

The Role of Potassium Channels in Arabidopsis thaliana Long Distance Electrical Signalling: AKT2 Modulates Tissue Excitability While GORK Shapes Action Potentials.

PubMed

Cuin, Tracey Ann; Dreyer, Ingo; Michard, Erwan

2018-03-21

Fast responses to an external threat depend on the rapid transmission of signals through a plant. Action potentials (APs) are proposed as such signals. Plant APs share similarities with their animal counterparts; they are proposed to depend on the activity of voltage-gated ion channels. Nonetheless, despite their demonstrated role in (a)biotic stress responses, the identities of the associated voltage-gated channels and transporters remain undefined in higher plants. By demonstrating the role of two potassium-selective channels in Arabidopsis thaliana in AP generation and shaping, we show that the plant AP does depend on similar Kv -like transport systems to those of the animal signal. We demonstrate that the outward-rectifying potassium-selective channel GORK limits the AP amplitude and duration, while the weakly-rectifying channel AKT2 affects membrane excitability. By computational modelling of plant APs, we reveal that the GORK activity not only determines the length of an AP but also the steepness of its rise and the maximal amplitude. Thus, outward-rectifying potassium channels contribute to both the repolarisation phase and the initial depolarisation phase of the signal. Additionally, from modelling considerations we provide indications that plant APs might be accompanied by potassium waves, which prime the excitability of the green cable.

Immunomodulatory therapies for acute pancreatitis

PubMed Central

Li, Jing; Yang, Wen-Juan; Huang, Lu-Ming; Tang, Cheng-Wei

2014-01-01

It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3rd d to the 14th d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis. PMID:25493006

Phase correlated adequate afferent action potentials as a drive of human spinal oscillators.

PubMed

Schalow, G

1993-12-01

1. By recording, with 2 pairs of wire electrodes, single-fibre action potentials (APs) from lower sacral nerve roots of a brain-dead human and a patient with spinal cord lesion, impulse patterns of afferent APs and impulse trains of oscillatory firing motoneurons could be identified and correlated. 2. Two highly activated secondary muscle spindle afferents increased and decreased their activity at about 0.3 Hz. The duration of the doublet interspike interval of a secondary spindle afferent fibre showed no correlation to the oscillation period of the motoneuron. 3. A continuously oscillatory firing motoneuron innervating the external and sphincter showed more transient breaks with the reduction of the number of phase correlated APs from 2 spindle afferents, indicating a looser oscillation. A transient brake of a 157 msec period alpha 2-oscillation could be correlated to the shift of a interspike interval distribution peak from 150 to 180 msec of the adequate afferent input, which suggests a transient loss of the necessary phase relation. 4. Oscillatory firing alpha 2-motoneurons innervating the external bladder and anal sphincters fired independently according to their phase correlated APs from the urinary bladder stretch receptor and muscle spindle afferents respectively; the bladder motoneuron slightly inhibited the anal motoneuron. 5. Receptors of the afferents and innervation sites of oscillatory firing motoneurons could be located within the urinary tract and the anal canal.

[Action of red polarized light on the acupuncture point E-36 increases analgesic effect of corvitin].

PubMed

Tamarova, Z A; Lymans'kyĭ, Iu P; Kostiuk, O I; Mitruzaeva, V A; Lymans'ka, L I

2010-01-01

In experiments on mice of lines C57BL/6J and CBA/CaLac, the possibility of strengthening of analgesic effect of corvitin by the action of red polarized light (PL) on the acupoint (AP) E-36 was studied. The pain behavioral response (licking of the painful area) was caused by injection of 5% formalin in hind limb (0.25 microl subcutaneously). The duration of pain response was studied before and after systemic introduction of corvitin (10 mg/kg, intraperitoneal) or joint use of corvitin and red PL (10 minute session). It is established, that after application of red PL on the antinociceptive AP E-36 in all animals an authentic strengthening of antinociceptive effect of corvitin takes place. In C57BL/6J mice, application of corvitin alone weakened the pain response by 29.7% and during combined use of red PL and corvitin, it grew up to 53.1%. Mice of line CBA/CaLac were less sensitive both to corvitin, and PL. In this line, corvitin used alone reduced the duration of pain response by 14%, and by 32.4% during combined use with red PL. Non-traumatic, without side effects, the method of influence by low-intensive PL can be recommended to patients accepting corvitin for strengthening its efficiency.

Effectiveness and clinical predictors of response to combined ECT and antipsychotic therapy in patients with treatment-resistant schizophrenia and dominant negative symptoms.

PubMed

Pawełczyk, Tomasz; Kołodziej-Kowalska, Emilia; Pawełczyk, Agnieszka; Rabe-Jabłońska, Jolanta

2014-12-15

The effectiveness and predictors of response to electroconvulsive therapy (ECT) combined with antipsychotics (AP) in treatment-resistant schizophrenia patients with the dominance of negative symptoms (TRS-NS) have not been studied systematically so far. 29 patients aged 21-55 years diagnosed with TRS-NS underwent ECT combined with antipsychotics (ECT+AP). Prior to the ECT, the symptom profile and severity were evaluated using Positive and Negative Syndrome Scale (PANSS). Demographic and medical data was collected; ECT parameters and pharmacotherapy results were evaluated. After the combined ECT+AP therapy a significant decrease in symptom severity was found. A response to treatment was achieved by 60% of patients. The greatest reductions were obtained in general and positive PANSS subscale (median change: 11 and 7 pts.) and the smallest, but still significant, ones in negative symptoms subscale (median: 3.5 pts.). Patients who responded to ECT+AP demonstrated a significantly shorter duration of the current episode in comparison with patients who did not experience at least a 25% reduction in symptom severity (median: 4 vs. 8 months). A combination of ECT and antipsychotic therapy can provide a useful treatment option for patients with TRS-NS. The only significant predictor of response to treatment was a shorter duration of the current episode. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Electrophysiological and structural determinants of electrotonic modulation of repolarization by the activation sequence

PubMed Central

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

Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments.

PubMed

Lambert, C S; Philpot, R M; Engberg, M E; Johns, B E; Wecker, L

2015-09-15

Studies have demonstrated that administration of the neuronal nicotinic receptor agonist varenicline to rats with olivocerebellar lesions attenuates balance deficits on a rotorod and balance beam, but the effects of this drug on gait deficits have not been investigated. To accomplish this, male Sprague-Dawley rats were trained to walk on a motorized treadmill at 25 and 35 cm/s and baseline performance determined; both temporal and spatial gait parameters were analyzed. A principal component analysis (PCA) was used to identify the key components of gait, and the cumulative gait index (CGI) was calculated, representing deviations from prototypical gait patterns. Subsequently, animals either remained as non-lesioned controls or received injections of 3-acetylpyridine (3-AP)/nicotinamide to destroy the climbing fibers innervating Purkinje cells. The gait of the non-lesioned group was assessed weekly to monitor changes in the normal population, while the gait of the lesioned group was assessed 1 week following 3-AP administration, and weekly following the daily administration of saline or varenicline (0.3, 1.0, or 3.0mg free base/kg) for 2 weeks. Non-lesioned animals exhibited a 60-70% increased CGI over time due to increases in temporal gait measures, whereas lesioned animals exhibited a nearly 3-fold increased CGI as a consequence of increases in spatial measures. Following 2 weeks of treatment with the highest dose of varenicline (3.0mg free base/kg), the swing duration of lesioned animals normalized, and stride duration, stride length and step angle in this population did not differ from the non-lesioned population. Thus, varenicline enabled animals to compensate for their impairments and rectify the timing of the gait cycle. Copyright © 2015 Elsevier B.V. All rights reserved.

Comparative benefit of malaria chemoprophylaxis modelled in United Kingdom travellers.

PubMed

Toovey, Stephen; Nieforth, Keith; Smith, Patrick; Schlagenhauf, Patricia; Adamcova, Miriam; Tatt, Iain; Tomianovic, Danitza; Schnetzler, Gabriel

2014-01-01

Chemoprophylaxis against falciparum malaria is recommended for travellers from non-endemic countries to malarious destinations, but debate continues on benefit, especially with regard to mefloquine. Quantification of benefit for travellers from the United Kingdom (UK) was modelled to assist clinical and public health decision making. The model was constructed utilising: World Tourism Organization data showing total number of arrivals from the UK in countries with moderate or high malaria risk; data from a retrospective UK Clinical Practice Research Datalink (CPRD) drug utilisation study; additional information on chemoprophylaxis, case fatality and tolerability were derived from the travel medicine literature. Chemoprophylaxis with the following agents was considered: atovaquone-proguanil (AP), chloroquine with and without proguanil (C ± P), doxycycline (Dx), mefloquine (Mq). The model was validated for the most recent year with temporally matched datasets for UK travel destinations and imported malaria (2007) against UK Health Protection Agency data on imported malaria. The median (mean) duration of chemoprophylaxis for each agent in weeks (CPRD) was: AP 3.3 (3.5), C ± P 9 (12.1), Dx 8 (10.3), Mq 9 (12.3): the maximum duration of use of all regimens was 52 weeks. The model correctly predicted falciparum malaria deaths and gave a robust estimate of total cases--model: 5 deaths from 1118 cases; UK Health Protection Agency: 5 deaths from 1153 cases. The number needed to take chemoprophylaxis (NNP) to prevent a case of malaria considered against the 'background' reported incidence in non-users of chemoprophylaxis deemed in need of chemoprophylaxis was: C ± P 272, Dx 269, Mq 260, AP 252; the NNP to prevent a UK traveller malaria death was: C ± P 62613, Dx 61923, Mq 59973, AP 58059; increasing the 'background' rate by 50% yielded NNPs of: C ± P 176, Dx 175, Mq 171, AP 168. The impact of substituting atovaquone-proguanil for all mefloquine usage resulted in a 2.3% decrease in estimated infections. The number of travellers experiencing moderate adverse events (AE) or those requiring medical attention or drug withdrawal per case prevented is as follows: C ± P 170, Mq 146, Dx 114, AP 103. The model correctly predicted the number of malaria deaths, providing a robust and reliable estimate of the number of imported malaria cases in the UK, and giving a measure of benefit derived from chemoprophylaxis use against the likely adverse events generated. Overall numbers needed to prevent a malaria infection are comparable among the four options and are sensitive to changes in the background infection rates. Only a limited impact on the number of infections can be expected if Mq is substituted by AP.

Evaluation of eye metrics as a detector of fatigue.

PubMed

McKinley, R Andy; McIntire, Lindsey K; Schmidt, Regina; Repperger, Daniel W; Caldwell, John A

2011-08-01

This study evaluated oculometrics as a detector of fatigue in Air Force-relevant tasks after sleep deprivation. Using the metrics of total eye closure duration (PERCLOS) and approximate entropy (ApEn), the relation between these eye metrics and fatigue-induced performance decrements was investigated. One damaging effect to the successful outcome of operational military missions is that attributed to sleep deprivation-induced fatigue. Consequently, there is interest in the development of reliable monitoring devices that can assess when an operator is overly fatigued. Ten civilian participants volunteered to serve in this study. Each was trained on three performance tasks: target identification, unmanned aerial vehicle landing, and the psychomotor vigilance task (PVT). Experimental testing began after 14 hr awake and continued every 2 hr until 28 hr of sleep deprivation was reached. Performance on the PVT and target identification tasks declined significantly as the level of sleep deprivation increased.These performance declines were paralleled more closely by changes in the ApEn compared to the PERCLOS measure. The results provide evidence that the ApEn eye metric can be used to detect fatigue in relevant military aviation tasks. Military and commercial operators could benefit from an alertness monitoring device.

Statistical Aspects of X-Class Halo and Non-Halo Events, 1996-2014

NASA Technical Reports Server (NTRS)

Wilson, Robert M.

2016-01-01

Of the 166 X-class events that occurred during the interval 1996-2014, 80 had associations with halo events, 68 had no associations with halo events, and 18 occurred during LASCO (Large Angle and Spectrometric COronagraph) data gaps. Both the duration and location of the X-class halo events proved to be statistically important parameters with respect to the geo-effectiveness of the events. Forty-four of the 80 X-class halo events occurred within 45 degrees of the Sun's central meridian and 47 of the 80 had duration greater than or equal to 30 minutes, whereas only 28 of the 68 X-class non-halo events occurred within 45 degrees of the Sun's central meridian (2 events have unknown location) and 22 of the 68 had duration greater than or equal to 30 minutes. Ignoring the 4 largest X-class flares greater than or equal to X4.0 during the LASCO data gaps, 17 of the remaining 20 were associated with halo events, and 14 of the 17 had at least one geo-magnetically disturbed day (Ap (i.e. NOAA's Ap* (ApStar)index: the major magnetic storms going back to 1932) greater than or equal to 25 nanotesias) within 1-5 days following the X-class halo event. Based on the hourly Dst (Disturbance storm time) index, the most geo-effective X-class halo event during the interval 1996-2014 was that of an X1.7 flare that occurred on 2001 March 29 at 0957, having an hourly Disturbance storm time minimum equal to minus 387 nanotesias. On average, the X-class halo events (80 events) were found to have a mean duration (42 minutes) slightly longer than the mean duration (29 minutes) of the X-class non-halo events (68 events) with the difference in the means being statistically important at the 1 percent level of significance.

To establish a pharmacological experimental platform for the study of cardiac hypoxia using the microelectrode array.

PubMed

Yeung, Chi-Kong; Sommerhage, Frank; Wrobel, Günter; Law, Jessica Ka-Yan; Offenhäusser, Andreas; Rudd, John Anthony; Ingebrandt, Sven; Chan, Mansun

2009-01-01

Simultaneous recording of electrical potentials from multiple cells may be useful for physiological and pharmacological research. The present study aimed to establish an in vitro cardiac hypoxia experimental platform on the microelectrode array (MEA). Embryonic rat cardiac myocytes were cultured on the MEAs. Following >or=90 min of hypoxia, changes in lactate production (mM), pH, beat frequency (beats per min, bpm), extracellular action potential (exAP) amplitude, and propagation velocity between the normoxic and hypoxic cells were compared. Under hypoxia, the beat frequency of cells increased and peaked at around 42.5 min (08.1+/-3.2 bpm). The exAP amplitude reduced as soon as the cells were exposed to the hypoxic medium, and this reduction increased significantly after approximately 20 min of hypoxia. The propagation velocity of the hypoxic cells was significantly lower than that of the control throughout the entire 90+ min of hypoxia. The rate of depolarisation and Na(+) signal gradually reduced over time, and these changes had a direct effect on the exAP duration. The extracellular electrophysiological measurements allow a partial reconstruction of the signal shape and time course of the underlying hypoxia-associated physiological changes. The present study showed that the cardiac myocyte-integrated MEA may be used as an experimental platform for the pharmacological studies of cardiovascular diseases in the future.

Electrophysiological mechanisms of sophocarpine as a potential antiarrhythmic agent.

PubMed

Yang, Zhi-fang; Li, Ci-zhen; Wang, Wei; Chen, Ying-min; Zhang, Ying; Liu, Yuan-mou; Wang, Hong-wei

2011-03-01

To examine the electrophysiological effects of sophocarpine on action potentials (AP) and ionic currents of cardiac myocytes and to compare some of these effects with those of amiodarone. Langendorff perfusion set-up was used in isolated guinea pig heart, and responses to sophocarpine were monitored using electrocardiograph. Conventional microelectrode, voltage clamp technique and perforated patch were employed to record fast response AP (fAP), slow response AP (sAP) and ionic currents in guinea pig papillary muscle or rabbit sinus node cells. Tachyarrhythmia produced by isoprenaline (15 μmol/L) could be reversed by sophocarpine (300 μmol/L). Sophocarpine (10 μmol/L) decreased the amplitude by 4.0%, maximal depolarization velocity (V(max)) of the fAP by 24.4%, and Na(+) current (I(Na)) by 18.0%, while it prolonged the effective refractory period (ERP) by 21.1%. The same concentration of sophocarpine could also decrease the amplitude and V(max) of the sAP, by 26.8% and 25.7%, respectively, and attenuated the Ca(2+) current (I(CaL)) and the K(+) tail current substantially. Comparison of sophocarpine with amiodarone demonstrated that both prolonged the duration and the ERP of fAP and sAP, both decreased the amplitude and V(max) of the fAP and sAP, and both slowed the automatic heart rate. Sophocarpine could reverse isoprenaline-induced arrhythmia and inhibit I(Na), I(CaL), and I(Kr) currents. The electrophysiological effects of sophocarpine are similar to those of amiodarone, which might be regarded as a prospective antiarrhythmic agent.

Genetic engineering of somatic cells to study and improve cardiac function.

PubMed

Kirkton, Robert D; Bursac, Nenad

2012-11-01

To demonstrate the utility of genetically engineered excitable cells for studies of basic electrophysiology and cardiac cell therapy. 'Zig-zag' networks of neonatal rat ventricular myocytes (NRVMs) were micropatterned onto thin elastomeric films to mimic the slow action potential (AP) conduction found in fibrotic myocardium. Addition of genetically engineered excitable human embryonic kidney cells (HEK-293 cells) ('Ex-293' cells stably expressing Kir2.1, Na(v)1.5, and Cx43 channels) increased both cardiac conduction velocity by 370% and twitch force amplitude by 64%. Furthermore, we stably expressed mutant Na(v)1.5 [A1924T (fast sodium channel mutant (substitution of alanine by threonine at amino acid 1924)] channels with hyperpolarized steady-state activation and showed that, despite a 71.6% reduction in peak I(Na), these cells propagated APs at the same velocity as the wild-type Na(v)1.5-expressing Ex-293 cells. Stable expression of Ca(v)3.3 (T-type voltage-gated calcium) channels in Ex-293 cells (to generate an 'ExCa-293' line) significantly increased their AP duration and reduced repolarization gradients in cocultures of these cells and NRVMs. Additional expression of an optogenetic construct [ChIEF (light-gated Channelrhodopsin mutant)]enabled light-based control of AP firing in ExCa-293 cells. We show that, despite being non-contractile, genetically engineered excitable cells can significantly improve both electrical and mechanical function of engineered cardiac tissues in vitro. We further demonstrate the utility of engineered cells for tissue-level studies of basic electrophysiology and cardiac channelopathies. In the future, this novel platform could be utilized in the high-throughput design of new genetically encoded indicators of cell electrical function, validation, and improvement of computer models of AP conduction, and development of novel engineered somatic cell therapies for the treatment of cardiac infarction and arrhythmias.

Ratio of cyclase activating and cyclase inactive parathormone (CAP/CIP) in dialysis patients: correlations with other markers of bone disease.

PubMed

Grzegorzewska, A E; Młot, M

2004-01-01

We checked correlation of CAP/CIP with osteoprotegrin (OPG), its soluble ligand (OPGL) and routinely measured parameters of bone turnover in patients treated with peritoneal dialysis (PD) and hemodialysis (HD). In 30 patients (22 HD, 8 PD) we determined serum concentrations of intact parathormone (iPTH), CAP, OPG, OPGL, total Ca, inorganic phosphates (Pi), creatinine, urea, total alkaline phosphatase (AP) and blood pH. CIP was calculated by subtraction of CAP from iPTH. Controls (Cs) included 9 healthy persons in whom iPTH, CAP, OPG and OPGL were measured as well as CIP, CAP/CIP and OPGL/OPG were calculated. Differences between HD and PD patients included dialysis duration, OPGL, OPGL/OPG, AP, Pi, Ca and pH. After adjustment to dialysis duration differences in OPGL/OPG, Pi, Ca and pH remained significant. HD patients differed from Cs in terms of iPTH, CAP, CIP, OPGL, OPG and OPGL/OPG. In whole group of patients iPTH, CAP, CIP but not CAP/CIP correlated negatively with OPGL and OPGL/OPG as well as positively with dialysis duration, OPG and AP. Despite more advanced uremic bone disease in longer dialyzed HD patients than in shorter dialyzed PD ones, CAP/CIP is not different neither between these groups nor Cs persons. CAP/CIP does not seem to be more powerful tool in noninvasive diagnosis of bone disease than iPTH or CAP and CIP alone.

Automated blood glucose control in type 1 diabetes: A review of progress and challenges.

PubMed

Bertachi, Arthur; Ramkissoon, Charrise M; Bondia, Jorge; Vehí, Josep

2018-03-01

Since the 2000s, research teams worldwide have been working to develop closed-loop (CL) systems able to automatically control blood glucose (BG) levels in patients with type 1 diabetes. This emerging technology is known as artificial pancreas (AP), and its first commercial version just arrived in the market. The main objective of this paper is to present an extensive review of the clinical trials conducted since 2011, which tested various implementations of the AP for different durations under varying conditions. A comprehensive table that contains key information from the selected publications is provided, and the main challenges in AP development and the mitigation strategies used are discussed. The development timelines for different AP systems are also included, highlighting the main evolutions over the clinical trials for each system. Copyright © 2017 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

Audio-visual interactions uniquely contribute to resolution of visual conflict in people possessing absolute pitch.

PubMed

Kim, Sujin; Blake, Randolph; Lee, Minyoung; Kim, Chai-Youn

2017-01-01

Individuals possessing absolute pitch (AP) are able to identify a given musical tone or to reproduce it without reference to another tone. The present study sought to learn whether this exceptional auditory ability impacts visual perception under stimulus conditions that provoke visual competition in the form of binocular rivalry. Nineteen adult participants with 3-19 years of musical training were divided into two groups according to their performance on a task involving identification of the specific note associated with hearing a given musical pitch. During test trials lasting just over half a minute, participants dichoptically viewed a scrolling musical score presented to one eye and a drifting sinusoidal grating presented to the other eye; throughout the trial they pressed buttons to track the alternations in visual awareness produced by these dissimilar monocular stimuli. On "pitch-congruent" trials, participants heard an auditory melody that was congruent in pitch with the visual score, on "pitch-incongruent" trials they heard a transposed auditory melody that was congruent with the score in melody but not in pitch, and on "melody-incongruent" trials they heard an auditory melody completely different from the visual score. For both groups, the visual musical scores predominated over the gratings when the auditory melody was congruent compared to when it was incongruent. Moreover, the AP participants experienced greater predominance of the visual score when it was accompanied by the pitch-congruent melody compared to the same melody transposed in pitch; for non-AP musicians, pitch-congruent and pitch-incongruent trials yielded equivalent predominance. Analysis of individual durations of dominance revealed differential effects on dominance and suppression durations for AP and non-AP participants. These results reveal that AP is accompanied by a robust form of bisensory interaction between tonal frequencies and musical notation that boosts the salience of a visual score.

Audio-visual interactions uniquely contribute to resolution of visual conflict in people possessing absolute pitch

PubMed Central

Kim, Sujin; Blake, Randolph; Lee, Minyoung; Kim, Chai-Youn

2017-01-01

Individuals possessing absolute pitch (AP) are able to identify a given musical tone or to reproduce it without reference to another tone. The present study sought to learn whether this exceptional auditory ability impacts visual perception under stimulus conditions that provoke visual competition in the form of binocular rivalry. Nineteen adult participants with 3–19 years of musical training were divided into two groups according to their performance on a task involving identification of the specific note associated with hearing a given musical pitch. During test trials lasting just over half a minute, participants dichoptically viewed a scrolling musical score presented to one eye and a drifting sinusoidal grating presented to the other eye; throughout the trial they pressed buttons to track the alternations in visual awareness produced by these dissimilar monocular stimuli. On “pitch-congruent” trials, participants heard an auditory melody that was congruent in pitch with the visual score, on “pitch-incongruent” trials they heard a transposed auditory melody that was congruent with the score in melody but not in pitch, and on “melody-incongruent” trials they heard an auditory melody completely different from the visual score. For both groups, the visual musical scores predominated over the gratings when the auditory melody was congruent compared to when it was incongruent. Moreover, the AP participants experienced greater predominance of the visual score when it was accompanied by the pitch-congruent melody compared to the same melody transposed in pitch; for non-AP musicians, pitch-congruent and pitch-incongruent trials yielded equivalent predominance. Analysis of individual durations of dominance revealed differential effects on dominance and suppression durations for AP and non-AP participants. These results reveal that AP is accompanied by a robust form of bisensory interaction between tonal frequencies and musical notation that boosts the salience of a visual score. PMID:28380058

Effects of seasonal acclimatization on temperature dependence of cardiac excitability in the roach, Rutilus rutilus.

PubMed

Badr, A; El-Sayed, M F; Vornanen, M

2016-05-15

Temperature sensitivity of electrical excitability is a potential limiting factor for performance level and thermal tolerance of excitable tissues in ectothermic animals. To test whether the rate and rhythm of the heart acclimatize to seasonal temperature changes, thermal sensitivity of cardiac excitation in a eurythermal teleost, the roach (Rutilus rutilus), was examined. Excitability of the heart was determined from in vivo electrocardiograms and in vitro microelectrode recordings of action potentials (APs) from winter and summer roach acclimatized to 4 and 18°C, respectively. Under heat ramps (3°C h(-1)), starting from the acclimatization temperatures of the fish, heart rate increased to maximum values of 78±5 beats min(-1) (at 19.8±0.5°C) and 150±7 beats min(-1) (at 28.1±0.5°C) for winter and summer roach, respectively, and then declined in both groups. Below 20°C, heart rate was significantly higher in winter than in summer roach (P<0.05), indicating positive thermal compensation. Cardiac arrhythmias appeared with rising temperature as missing QRS complexes, increase in variability of heart rate, episodes of atrial tachycardia, ventricular bradycardia and complete cessation of the heartbeat (asystole) in both winter and summer roach. Unlike winter roach, atrial APs of summer roach had a distinct early repolarization phase, which appeared as shorter durations of atrial AP at 10% and 20% repolarization levels in comparison to winter roach (P<0.05). In contrast, seasonal acclimatization had only subtle effects on ventricular AP characteristics. Plasticity of cardiac excitation appears to be necessary for seasonal improvements in performance level and thermal resilience of the roach heart. © 2016. Published by The Company of Biologists Ltd.

Effects of Nicotinamide Adenine Dinucleotide (NAD(+)) and Diadenosine Tetraphosphate (Ap4A) on Electrical Activity of Working and Pacemaker Atrial Myocardium in Guinea Pigs.

PubMed

Pustovit, K B; Abramochkin, D V

2016-04-01

Effects of nucleotide polyphosphate compounds (nicotinamide adenine dinucleotide, NAD(+); diadenosine tetraphosphate, Ap4A) on the confi guration of action potentials were studied in isolated preparations of guinea pig sinoatrial node and right atrial appendage (auricle). In the working myocardium, NAD(+) and Ap4A in concentrations of 10(-5) and 10(-4) M had no effect on resting potential, but significantly reduced the duration of action potentials; the most pronounced decrease was found at 25% repolarization. In the primary pacemaker of the sinoatrial node, both concentrations of NAD(+) and Ap4A induced hyperpolarization and reduction in the rate of slow diastolic depolarization, but significant slowing of the sinus rhythm was produced by these substances only in the concentration of 10(-4) M. Moreover, AP shortening and marked acceleration of AP upstroke were observed in the pacemaker myocardium after application of polyphosphates. Comparative analysis of the effects of NAD(+) and Ap4A in the working and pacemaker myocardium drove us to a hypothesis on inhibitory effects of these substances on L-type calcium current accompanied by stimulation of one or several potassium currents, which induce enhancement of repolarization and hyperpolarization of membranes probably mediated by the activation of purine receptors.

Acute Pancreatitis and Use of Pancreatitis-Associated Drugs: A 10-Year Population-Based Cohort Study.

PubMed

Bertilsson, Sara; Kalaitzakis, Evangelos

2015-10-01

To assess the use of acute pancreatitis (AP)-associated drugs in patients with AP, the relation between sales of these drugs and the incidence of AP, and the potential impact on AP severity and recurrence. All patients with incident AP between 2003 and 2012, in a well-defined area, were retrospectively identified. Data regarding AP etiology, severity, and recurrence and use of AP-associated drugs were extracted from medical records. Drugs were classified according to an evidence-based classification system. Annual drug sales data were obtained from the Swedish drug administration service. Overall, 1457 cases of incident AP were identified. Acute pancreatitis-associated drug users increased from 32% in 2003 to 51% in 2012, reflecting increasing user rates in the general population. The incidence of AP increased during the study period but was not related to AP-associated drug user rates (P > 0.05). Recurrent AP occurred in 23% but was unrelated to AP-associated drug use (P > 0.05). In logistic regression analysis, after adjustment for comorbidity, AP-associated drug use was not related to AP severity (P > 0.05). Use of AP-associated drugs is increasingly frequent in patients with AP. However, it does not have any major impact on the observed epidemiological changes in occurrence, severity, or recurrence of AP.

STREAK CAMERA MEASUREMENTS OF THE APS PC GUN DRIVE LASER

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

Dooling, J. C.; Lumpkin, A. H.

We report recent pulse-duration measurements of the APS PC Gun drive laser at both second harmonic and fourth harmonic wavelengths. The drive laser is a Nd:Glass-based chirped pulsed amplifier (CPA) operating at an IR wavelength of 1053 nm, twice frequency-doubled to obtain UV output for the gun. A Hamamatsu C5680 streak camera and an M5675 synchroscan unit are used for these measurements; the synchroscan unit is tuned to 119 MHz, the 24th subharmonic of the linac s-band operating frequency. Calibration is accomplished both electronically and optically. Electronic calibration utilizes a programmable delay line in the 119 MHz rf path. Themore » optical delay uses an etalon with known spacing between reflecting surfaces and is coated for the visible, SH wavelength. IR pulse duration is monitored with an autocorrelator. Fitting the streak camera image projected profiles with Gaussians, UV rms pulse durations are found to vary from 2.1 ps to 3.5 ps as the IR varies from 2.2 ps to 5.2 ps.« less

High incidence of athletic pubalgia symptoms in professional athletes with symptomatic femoroacetabular impingement.

PubMed

Hammoud, Sommer; Bedi, Asheesh; Magennis, Erin; Meyers, William C; Kelly, Bryan T

2012-10-01

The purpose of this study was to identify the incidence of symptoms consistent with athletic pubalgia (AP) in athletes requiring surgical treatment for femoroacetabular impingement (FAI) and the frequency of surgical treatment of both AP and FAI in this group of patients. Thirty-eight consecutive professional athletes, with a mean age of 31 years, underwent arthroscopic surgery for symptomatic FAI that limited their ability to play competitively. In all cases a cam and/or focal rim osteoplasty with labral refixation or debridement was performed. In 1 case concomitant intramuscular lengthening of the psoas was performed. Retrospective data regarding prior AP surgery and return to play were collected. Thirty-two percent of patients had previously undergone AP surgery, and 1 patient underwent AP surgery concomitantly with surgical treatment of FAI. No patient returned to his previous level of competition after isolated AP surgery. Thirty-nine percent had AP symptoms that resolved with FAI surgery alone. Of the 38 patients, 36 returned to their previous level of play; all 12 patients with combined AP and FAI surgery returned to professional competition. The mean duration before return to play was 5.9 months (range, 3 to 9 months) after arthroscopic surgery. There is a high incidence of symptoms of AP in professional athletes with FAI of the hip. This study draws attention to the overlap of these 2 diagnoses and highlights the importance of exercising caution in diagnosing AP in a patient with FAI. Level IV, therapeutic, retrospective case series. Copyright © 2012 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Empirical radiation belt models: Comparison with in situ data and implications for environment definition

NASA Astrophysics Data System (ADS)

de Soria-Santacruz Pich, Maria; Jun, Insoo; Evans, Robin

2017-09-01

The empirical AP8/AE8 model has been the de facto Earth's radiation belts engineering reference for decades. The need from the community for a better model incubated the development of AP9/AE9/SPM, which addresses several shortcomings of the old model. We provide additional validation of AP9/AE9 by comparing in situ electron and proton data from Jason-2, Polar Orbiting Environmental Satellites (POES), and the Van Allen Probes spacecraft with the 5th, 50th, and 95th percentiles from AE9/AP9 and with the model outputs from AE8/AP8. The relatively short duration of Van Allen Probes and Jason-2 missions means that their measurements are most certainly the result of specific climatological conditions. In low Earth orbit (LEO), the Jason-2 proton flux is better reproduced by AP8 compared to AP9, while the POES electron data are well enveloped by AE9 5th and 95th percentiles. The shape of the South Atlantic anomaly (SAA) from Jason-2 data is better captured by AP9 compared to AP8, while the peak SAA flux is better reproduced by AP8. The <1.5 MeV inner belt electrons from Magnetic Electron Ion Spectrometer (MagEIS) are well enveloped by AE9 5th and 95th percentiles, while AE8 overpredicts the measurements. In the outer radiation belt, MagEIS and Relativistic Electron and Proton Telescope (REPT) electrons closely follow the median estimate from AE9, while AP9 5th and 95th percentiles generally envelope REPT proton measurements in the inner belt and slot regions. While AE9/AP9 offer the flexibility to specify the environment with different confidence levels, the dose and trapped proton peak flux for POES and Jason-2 trajectories from the AE9/AP9 50th percentile and above are larger than the estimates from the AE8/AP8 models.

Sex Differences in β-Adrenergic Responsiveness of Action Potentials and Intracellular Calcium Handling in Isolated Rabbit Hearts

PubMed Central

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

The natriuretic peptides BNP and CNP increase heart rate and electrical conduction by stimulating ionic currents in the sinoatrial node and atrial myocardium following activation of guanylyl cyclase-linked natriuretic peptide receptors.

PubMed

Springer, Jeremy; Azer, John; Hua, Rui; Robbins, Courtney; Adamczyk, Andrew; McBoyle, Sarah; Bissell, Mary Beth; Rose, Robert A

2012-05-01

Natriuretic peptides (NPs) are best known for their ability to regulate blood vessel tone and kidney function whereas their electrophysiological effects on the heart are less clear. Here, we measured the effects of BNP and CNP on sinoatrial node (SAN) and atrial electrophysiology in isolated hearts as well as isolated SAN and right atrial myocytes from mice. BNP and CNP dose-dependently increased heart rate and conduction through the heart as indicated by reductions in R-R interval, P wave duration and P-R interval on ECGs. In conjunction with these ECG changes BNP and CNP (100 nM) increased spontaneous action potential frequency in isolated SAN myocytes by increasing L-type Ca(2+) current (I(Ca,L)) and the hyperpolarization-activated current (I(f)). BNP had no effect on right atrial myocyte APs in basal conditions; however, in the presence of isoproterenol (10nM), BNP increased atrial AP duration and I(Ca,L). Quantitative gene expression and immunocytochemistry data show that all three NP receptors (NPR-A, NPR-B and NPR-C) are expressed in the SAN and atrium. The effects of BNP and CNP on SAN and right atrial myocytes were maintained in mutant mice lacking functional NPR-C receptors and blocked by the NPR-A antagonist A71915 indicating that BNP and CNP function through their guanylyl cyclase-linked receptors. Our data also show that the effects of BNP and CNP are completely absent in the presence of the phosphodiesterase 3 inhibitor milrinone. Based on these data we conclude that NPs can increase heart rate and electrical conduction by activating the guanylyl cyclase-linked NPR-A and NPR-B receptors and inhibiting PDE3 activity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Treatment effect with paliperidone palmitate compared with oral antipsychotics in patients with recent-onset versus more chronic schizophrenia and a history of criminal justice system involvement.

PubMed

Alphs, Larry; Bossie, Cynthia; Mao, Lian; Lee, Erin; Starr, H Lynn

2018-02-01

Long-acting injectable antipsychotics (APs) are not well studied in recent-onset schizophrenia. This exploratory analysis of a study designed to reflect real-world schizophrenia, as defined by patients, interventions and outcomes, compared relative treatment effect between once-monthly paliperidone palmitate (PP) and daily oral APs in patients with recent-onset or chronic illness METHODS: This randomized, open-label, event monitoring board-blinded study compared treatment response in subjects with schizophrenia and a history of criminal justice system involvement following treatment with PP or oral APs for 15 months (ClinicalTrials.gov identifier, NCT01157351). Event-free probabilities were estimated using Kaplan-Meier method; hazard ratios (HRs) were estimated using Cox proportional hazard models. This subgroup analysis analysed data by disease duration (≤5 (recent-onset) or >5 years (chronic illness) since first psychiatric diagnosis). Seventy-seven subjects met the criteria for recent-onset illness; 365 for chronic illness. HRs (95% CI) for treatment failure for oral APs versus PP were 1.73 (0.87-3.45; P = 0.121) for recent-onset and 1.37 (1.02-1.85; P = 0.039) for chronic illness. Most common adverse events for PP versus oral APs were injection site pain (recent-onset, 26% vs. 0%; chronic, 17% vs. 0%), increased weight (14% vs. 6%; 12% vs. 6%), akathisia (14% vs. 9%; 10% vs. 7%), insomnia (12% vs. 17%; 18% vs. 10%) and anxiety (12% vs. 6%; 10% vs. 8%). Although neither pre-planned nor adequately powered, the estimated HRs suggest that the relative advantage of PP over oral APs for reducing the risk for treatment failure may be greater in patients with recent-onset schizophrenia than in those with more chronic illness. © 2015 The Authors. Early Intervention in Psychiatry published by Wiley Publishing Asia Pty Ltd.

Postflight Quiet Stance Stability of Astronauts Following Recovery From a Simulated Fall

NASA Technical Reports Server (NTRS)

Reschke, M. F.; Kofman, I. S.; Fisher, E. A.; Cerisano, J. M.; Lawrence, E. L.; Peters, B. T.; Harm, D. L.; Kulecz, W.; Mulavara, A. P.; Fiedler, M. J.;

Beta-blocking agents during electroconvulsive therapy: a review.

PubMed

Boere, E; Birkenhäger, T K; Groenland, T H N; van den Broek, W W

2014-07-01

Electroconvulsive therapy (ECT) is associated with at least transient episodes of hypertension and tachycardia. Beta-blocking agents may be indicated to prevent cardiovascular complications and may shorten seizure duration. This review evaluates studies that used beta-blocking agents during ECT to determine which agent has the most favourable outcomes on cardiovascular variables and seizure duration. A Medline database search was made using the combined keywords 'adrenergic beta-antagonists' and 'electroconvulsive therapy'. The search was restricted to double-blind randomized controlled trials and yielded 29 original studies. With the use of esmolol, significant attenuating effects were found on cardiovascular parameters in the first 5 min after stimulation; its shortening effects on seizure duration may be dose-related. With the use of labetalol, findings on cardiovascular effects were inconsistent during the first minutes after stimulation but were significant after 5 min and thereafter; seizure duration was scarcely studied. Landiolol attenuates heart rate but with inconsistent findings regarding arterial pressure (AP); seizure duration was mostly unaffected. Esmolol appears to be effective in reducing the cardiovascular response, although seizure duration may be affected with higher dosages. Landiolol can be considered a suitable alternative, but effects on AP need further investigation. Labetalol has been studied to a lesser extent and may have prolonged cardiovascular effects. The included studies varied in design, methodology, and the amount of exact data provided in the publications. Further study of beta-blocking agents in ECT is clearly necessary. © The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium.

PubMed

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.

Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea.

PubMed

Grinspoon, S; Miller, K; Coyle, C; Krempin, J; Armstrong, C; Pitts, S; Herzog, D; Klibanski, A

1999-06-01

Reduced bone density is observed in over half of women with anorexia nervosa (AN), in whom the risk of fracture is significantly increased even at a young age. It is unknown to what extent low bone density in AN differs from other conditions of premenopausal osteoporosis and is related to estrogen deficiency and/or other factors, such as nutritional status. We therefore investigated bone loss in nutritionally replete and nutritionally deplete amenorrheic women by comparing patients with AN (n = 30) to age-matched subjects with hypothalamic amenorrhea (HA; n = 19) in whom duration of amenorrhea, prior estrogen use, and age of menarche were comparable. Healthy, age-matched, eumenorrheic women were studied as a control group (NL; n = 30). Weight and nutritionally dependent factors including (body mass index, 20.7 +/- 0.3 vs. 16.7 +/- 0.3 kg/m2; P < 0.0001), insulin-like growth factor I (270 +/- 18 vs. 203 +/- 17 ng/mL; P < 0.01), percent body fat (26% vs. 19%; P < 0.0001), and lean body mass (38.7 +/- 1.1 vs. 34.3 +/- 0.8, P < 0.01) were significantly different between the HA and AN groups, respectively. The bone densities of the anterior-posterior (AP) spine, total hip, and total body measured by dual energy x-ray absortiometry were reduced in both amenorrheic groups compared to those in control subjects, but were significantly lower in women with AN than in those with HA. The t scores for AP spine and hip were -1.80 +/- 0.15 (AN), -0.80 +/- 0.22 (HA), and 0.28 +/- 0.19 SD (NL) for the AP spine and -1.62 +/- 0.17 (AN), -0.51 +/- 0.21 (HA), and 0.25 +/- 0.16 (NL) for the total hip, respectively (P < 0.01 for all comparisons). Among the amenorrheic subjects, duration of amenorrhea, age of menarche, and N-telopeptide were inversely correlated with bone density at all sites, whereas body mass index, insulin-like growth factor I, lean body mass, and fat intake were positively correlated with bone density at all sites measured. In multivariate regression analyses, bone density was most significantly related to lean body mass (P = 0.05 and P = 0.03 for the spine and hip, respectively), but not to the duration of amenorrhea or other indexes of estrogen status among patients with AN. In contrast, bone density of the lumbar spine was significantly related to weight and duration of amenorrhea among patients with HA. These data demonstrate that the severity of osteopenia in AN is greater than that in patients with HA and is critically dependent upon nutritional factors in addition to the degree or duration of estrogen deficiency itself. Lean body mass, independent of the duration or severity of estrogen deficiency, is an important predictor of bone loss among women with AN.

Two-Photon Na+ Imaging Reports Somatically Evoked Action Potentials in Rat Olfactory Bulb Mitral and Granule Cell Neurites.

PubMed

Ona-Jodar, Tiffany; Gerkau, Niklas J; Sara Aghvami, S; Rose, Christine R; Egger, Veronica

2017-01-01

Dendrodendritic synaptic interactions are a hallmark of neuronal processing in the vertebrate olfactory bulb. Many classes of olfactory bulb neurons including the principal mitral cells (MCs) and the axonless granule cells (GCs) dispose of highly efficient propagation of action potentials (AP) within their dendrites, from where they can release transmitter onto each other. So far, backpropagation in GC dendrites has been investigated indirectly via Ca 2+ imaging. Here, we used two-photon Na + imaging to directly report opening of voltage-gated sodium channels due to AP propagation in both cell types. To this end, neurons in acute slices from juvenile rat bulbs were filled with 1 mM SBFI via whole-cell patch-clamp. Calibration of SBFI signals revealed that a change in fluorescence Δ F / F by 10% corresponded to a Δ[Na + ] i of ∼22 mM. We then imaged proximal axon segments of MCs during somatically evoked APs (sAP). While single sAPs were detectable in ∼50% of axons, trains of 20 sAPs at 50 Hz always resulted in substantial Δ F / F of ∼15% (∼33 mM Δ[Na + ] i ). Δ F / F was significantly larger for 80 Hz vs. 50 Hz trains, and decayed with half-durations τ 1/2 ∼0.6 s for both frequencies. In MC lateral dendrites, AP trains yielded small Δ F / F of ∼3% (∼7 mM Δ[Na + ] i ). In GC apical dendrites and adjacent spines, single sAPs were not detectable. Trains resulted in an average dendritic Δ F / F of 7% (16 mM Δ[Na + ] i ) with τ 1/2 ∼1 s, similar for 50 and 80 Hz. Na + transients were indistinguishable between large GC spines and their adjacent dendrites. Cell-wise analysis revealed two classes of GCs with the first showing a decrease in Δ F / F along the dendrite with distance from the soma and the second an increase. These classes clustered with morphological parameters. Simulations of Δ[Na + ] i replicated these behaviors via negative and positive gradients in Na + current density, assuming faithful AP backpropagation. Such specializations of dendritic excitability might confer specific temporal processing capabilities to bulbar principal cell-GC subnetworks. In conclusion, we show that Na + imaging provides a valuable tool for characterizing AP invasion of MC axons and GC dendrites and spines.

Two-Photon Na+ Imaging Reports Somatically Evoked Action Potentials in Rat Olfactory Bulb Mitral and Granule Cell Neurites

PubMed Central

Ona-Jodar, Tiffany; Gerkau, Niklas J.; Sara Aghvami, S.; Rose, Christine R.; Egger, Veronica

2017-01-01

Dendrodendritic synaptic interactions are a hallmark of neuronal processing in the vertebrate olfactory bulb. Many classes of olfactory bulb neurons including the principal mitral cells (MCs) and the axonless granule cells (GCs) dispose of highly efficient propagation of action potentials (AP) within their dendrites, from where they can release transmitter onto each other. So far, backpropagation in GC dendrites has been investigated indirectly via Ca2+ imaging. Here, we used two-photon Na+ imaging to directly report opening of voltage-gated sodium channels due to AP propagation in both cell types. To this end, neurons in acute slices from juvenile rat bulbs were filled with 1 mM SBFI via whole-cell patch-clamp. Calibration of SBFI signals revealed that a change in fluorescence ΔF/F by 10% corresponded to a Δ[Na+]i of ∼22 mM. We then imaged proximal axon segments of MCs during somatically evoked APs (sAP). While single sAPs were detectable in ∼50% of axons, trains of 20 sAPs at 50 Hz always resulted in substantial ΔF/F of ∼15% (∼33 mM Δ[Na+]i). ΔF/F was significantly larger for 80 Hz vs. 50 Hz trains, and decayed with half-durations τ1/2 ∼0.6 s for both frequencies. In MC lateral dendrites, AP trains yielded small ΔF/F of ∼3% (∼7 mM Δ[Na+]i). In GC apical dendrites and adjacent spines, single sAPs were not detectable. Trains resulted in an average dendritic ΔF/F of 7% (16 mM Δ[Na+]i) with τ1/2 ∼1 s, similar for 50 and 80 Hz. Na+ transients were indistinguishable between large GC spines and their adjacent dendrites. Cell-wise analysis revealed two classes of GCs with the first showing a decrease in ΔF/F along the dendrite with distance from the soma and the second an increase. These classes clustered with morphological parameters. Simulations of Δ[Na+]i replicated these behaviors via negative and positive gradients in Na+ current density, assuming faithful AP backpropagation. Such specializations of dendritic excitability might confer specific temporal processing capabilities to bulbar principal cell-GC subnetworks. In conclusion, we show that Na+ imaging provides a valuable tool for characterizing AP invasion of MC axons and GC dendrites and spines. PMID:28293175

THE 4-AMINOPYRIDINE IN VITRO EPILEPSY MODEL ANALYZED WITH A PERFORATED MULTI-ELECTRODE ARRAY

PubMed Central

Gonzalez-Sulser, Alfredo; Wang, Jing; Motamedi, Gholam K.; Avoli, Massimo; Vicini, Stefano; Dzakpasu, Rhonda

2010-01-01

Epileptiform discharges recorded in the 4-aminopyridine (4-AP) in vitro epilepsy model are mediated by glutamatergic and GABAergic signaling. Using a 60-channel perforated multi-electrode array (pMEA) on corticohippocampal slices from 2 to 3 week old mice we recorded interictal- and ictal-like events. When glutamatergic transmission was blocked, interictal-like events events no longer initiated in the hilus or CA3/CA1 pyramidal layers but originated from the dentate gyrus granule and molecular layers. Furthermore, frequencies of interictal-like events were reduced and durations were increased in these regions while cortical discharges were completely blocked. Following GABAA receptor blockade interictal-like events no longer propagated to the dentate gyrus while their frequency in CA3 increased; in addition, ictal-like cortical events became shorter while increasing in frequency. Lastly, drugs that affect tonic and synaptic GABAergic conductance modulate the frequency, duration, initiation and propagation of interictal-like events. These findings confirm and expand on previous studies indicating that multiple synaptic mechanisms contribute to synchronize neuronal network activity in forebrain structures. PMID:20955719

Structural Brain Damage and Upper Limb Kinematics in Children with Unilateral Cerebral Palsy.

PubMed

Mailleux, Lisa; Simon-Martinez, Cristina; Klingels, Katrijn; Jaspers, Ellen; Desloovere, Kaat; Demaerel, Philippe; Fiori, Simona; Guzzetta, Andrea; Ortibus, Els; Feys, Hilde

2017-01-01

Background: In children with unilateral cerebral palsy (uCP) virtually nothing is known on the relation between structural brain damage and upper limb (UL) kinematics quantified with three-dimensional movement analysis (3DMA). This explorative study aimed to (1) investigate differences in UL kinematics between children with different lesion timings, i.e., periventricular white matter (PWM) vs. cortical and deep gray matter (CDGM) lesions and (2) to explore the relation between UL kinematics and lesion location and extent within each lesion timing group. Methods: Forty-eight children (age 10.4 ± 2.7 year; 29 boys; 21 right-sided; 33 PWM; 15 CDGM) underwent an UL 3DMA during a reach-to-grasp task. Spatiotemporal parameters [movement duration, (timing of) maximum velocity, trajectory straightness], the Arm Profile Score (APS) and Arm Variable Scores (AVS) were extracted. The APS and AVS refer to the total amount of movement pathology and movement deviations of the wrist, elbow, shoulder, scapula and trunk respectively. Brain lesion location and extent were scored based on FLAIR-images using a semi-quantitative MRI-scale. Results: Children with CDGM lesions showed more aberrant spatiotemporal parameters ( p < 0.03) and more movement pathology (APS, p = 0.003) compared to the PWM group, mostly characterized by increased wrist flexion ( p = 0.01). In the CDGM group, moderate to high correlations were found between lesion location and extent and duration, timing of maximum velocity and trajectory straightness ( r = 0.53-0.90). Lesion location and extent were further moderately correlated with distal UL movement pathology (wrist flexion/extension, elbow pronation/supination, elbow flexion/extension; r = 0.50-0.65) and with the APS ( r = 0.51-0.63). In the PWM group, only a few and low correlations were observed, mostly between damage to the PLIC and higher AVS of elbow flexion/extension, shoulder elevation and trunk rotation ( r = 0.35-0.42). Regression analysis revealed damage to the temporal lobe with lesion timing as interactor (27%, p = 0.002) and the posterior limb of the internal capsule (PLIC) (7%, p = 0.04) as the strongest predictors, explaining 34% of the variance in APS. Conclusion: UL kinematic deviations are more influenced by lesion location and extent in children with later (CDGM) versus earlier lesions (PWM), except for proximal movement pathology. Damage to the PLIC is a significant predictor for UL movement pathology irrespective of lesion timing.

Clinical significance of the summating potential-action potential ratio and the action potential latency difference for condensation and rarefaction clicks in Meniere's disease.

PubMed

Ohashi, Toru; Nishino, Hirohito; Arai, Yoko; Hyodo, Makoto; Takatsu, Mitsuharu

2009-04-01

This study was aimed to elucidate the diagnostic significance of the summating potential (SP)-action potential (AP) ratio and the AP latency difference between condensation and rarefaction clicks (AP con-rar difference) in Meniere's disease. The AP and SP were recorded transtympanically in 67 patients with definite Meniere's disease. The SP/AP ratio and the AP con-rar difference were assessed in terms of 1) their interrelationship, 2) their relationship to hearing level, and 3) the rate of occurrence of abnormal values according to the stages of Meniere's disease. No correlation was found between the SP/AP ratio and the AP con-rar difference. Neither the SP/AP ratio in general nor the AP con-rar difference was correlated with the hearing level. However, enhanced values of the SP/AP ratio (0.35 or higher) were moderately correlated with the hearing level (r = 0.51), and their occurrence rate was 55.2%. An increased AP con-rar difference (0.13 ms or longer) was not correlated with the hearing level, and its occurrence rate was 50.2%; it appeared most frequently at stage 3 (p <0.05). An enhanced SP/AP ratio might not always indicate the presence of endolymphatic hydrops associated with an increase in endolymphatic pressure. An increased AP con-rar difference might reflect the presence of a biased basilar membrane resulting from an increased endolymphatic pressure, and hence it is diagnostically essential to simultaneously evaluate the SP/AP ratio and the AP con-rar difference.

Intracranial bleeding: epidemiology and relationships with antithrombotic treatment in 241 cerebral hemorrhages in Reggio Emilia.

PubMed

Nicolini, Alberto; Ghirarduzzi, Angelo; Iorio, Alfonso; Silingardi, Mauro; Malferrari, Giovanni; Baldi, Giovanni

2002-09-01

Anticoagulant (AC) and antiplatelet (AP) drugs are effectively used in the prevention of thromboembolic events, with the trade-off of bleeding side effects, particularly intracranial. The aim of this study was to determine the incidence of intracranial bleeding in the population of Reggio Emilia and to investigate the potential effect of AC and AP drugs. We reviewed all the patients admitted for cerebral hemorrhages to our hospital between April 1998 and September 2000. Data were collected with a standardized form. All the patients were followed-up to estimate long-term mortality. Chi(2) and t-tests were used as appropriate. Logistic regression analysis was performed to test predictors of mortality. Pharmaceutical department data were employed to estimate the total number of patients receiving AC and AP drugs. We found 241 cases (107/134 female/male, mean age 61 years, 133/107 spontaneous/traumatic events, 0.32/1,000/year overall). Twenty-nine and 47 of these patients were being given AC or AP drugs, respectively (4.9/1,000/year and 3.7/1,000/year). The relative risk of intracranial bleeding was 11.5 in AP and 15.3 in AC treated patients. Two patients (one underwent neurosurgery and one thrombolytic treatment) were excluded from mortality and risk factors analysis. Six patients were lost from follow-up and excluded from mortality analysis. Overall mortality was 100/233 (42.9%); mortality in traumatic events was 25/103 (24.2%) versus 75/130 (57.7%) in spontaneous events. Mortality was 19/29 (65.5%), 26/47 (55.3%) and 55/157 (35%) in AC recipients, AP recipients, and untreated patients, respectively. This increased risk was mainly confined to traumatic events (p = 0.06), without difference between AC and AP recipients. At the time of the event, the mean duration of oral AC treatment was 26.3 months (range 1-120). Mean INR was = 3.1 (range 1.6-8.8). Mortality was significantly predicted by the Glasgow Coma Scale Score (GCS) at admission (p < 0.0001), by the type of bleeding (spontaneous versus traumatic) (p = 0.0026), and by age (p < 0.0001). Careful selection of patients and prevention of traumatic events are the main candidate mechanisms to reduce intracranial bleeding in patients being treated with AC and AP drugs.

A human ventricular cell model for investigation of cardiac arrhythmias under hyperkalaemic conditions.

PubMed

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.

Low Earth orbit assessment of proton anisotropy using AP8 and AP9 trapped proton models

NASA Astrophysics Data System (ADS)

Badavi, Francis F.; Walker, Steven A.; Santos Koos, Lindsey M.

2015-04-01

The completion of the International Space Station (ISS) in 2011 has provided the space research community with an ideal evaluation and testing facility for future long duration human activities in space. Ionized and secondary neutral particles radiation measurements inside ISS form the ideal tool for validation of radiation environmental models, nuclear reaction cross sections and transport codes. Studies using thermo-luminescent detectors (TLD), tissue equivalent proportional counter (TPEC), and computer aided design (CAD) models of early ISS configurations confirmed that, as input, computational dosimetry at low Earth orbit (LEO) requires an environmental model with directional (anisotropic) capability to properly describe the exposure of trapped protons within ISS. At LEO, ISS encounters exposure from trapped electrons, protons and geomagnetically attenuated galactic cosmic rays (GCR). For short duration studies at LEO, one can ignore trapped electrons and ever present GCR exposure contributions during quiet times. However, within the trapped proton field, a challenge arises from properly estimating the amount of proton exposure acquired. There exist a number of models to define the intensity of trapped particles. Among the established trapped models are the historic AE8/AP8, dating back to the 1980s and the recently released AE9/AP9/SPM. Since at LEO electrons have minimal exposure contribution to ISS, this work ignores the AE8 and AE9 components of the models and couples a measurement derived anisotropic trapped proton formalism to omnidirectional output from the AP8 and AP9 models, allowing the assessment of the differences between the two proton models. The assessment is done at a target point within the ISS-11A configuration (circa 2003) crew quarter (CQ) of Russian Zvezda service module (SM), during its ascending and descending nodes passes through the south Atlantic anomaly (SAA). The anisotropic formalism incorporates the contributions of proton narrow pitch angle (PA) and east-west (EW) effects. Within SAA, the EW anisotropy results in different level of exposure to each side of the ISS Zvezda SM, allowing angular evaluation of the anisotropic proton spectrum. While the combined magnitude of PA and EW effects at LEO depends on a multitude of factors such as trapped proton energy, orientation and altitude of the spacecraft along the velocity vector, this paper draws quantitative conclusions on the combined anisotropic magnitude differences within ISS SM target point between AP8 and AP9 models.

Low Earth orbit assessment of proton anisotropy using AP8 and AP9 trapped proton models.

PubMed

Badavi, Francis F; Walker, Steven A; Santos Koos, Lindsey M

2015-04-01

The completion of the International Space Station (ISS) in 2011 has provided the space research community with an ideal evaluation and testing facility for future long duration human activities in space. Ionized and secondary neutral particles radiation measurements inside ISS form the ideal tool for validation of radiation environmental models, nuclear reaction cross sections and transport codes. Studies using thermo-luminescent detectors (TLD), tissue equivalent proportional counter (TPEC), and computer aided design (CAD) models of early ISS configurations confirmed that, as input, computational dosimetry at low Earth orbit (LEO) requires an environmental model with directional (anisotropic) capability to properly describe the exposure of trapped protons within ISS. At LEO, ISS encounters exposure from trapped electrons, protons and geomagnetically attenuated galactic cosmic rays (GCR). For short duration studies at LEO, one can ignore trapped electrons and ever present GCR exposure contributions during quiet times. However, within the trapped proton field, a challenge arises from properly estimating the amount of proton exposure acquired. There exist a number of models to define the intensity of trapped particles. Among the established trapped models are the historic AE8/AP8, dating back to the 1980s and the recently released AE9/AP9/SPM. Since at LEO electrons have minimal exposure contribution to ISS, this work ignores the AE8 and AE9 components of the models and couples a measurement derived anisotropic trapped proton formalism to omnidirectional output from the AP8 and AP9 models, allowing the assessment of the differences between the two proton models. The assessment is done at a target point within the ISS-11A configuration (circa 2003) crew quarter (CQ) of Russian Zvezda service module (SM), during its ascending and descending nodes passes through the south Atlantic anomaly (SAA). The anisotropic formalism incorporates the contributions of proton narrow pitch angle (PA) and east-west (EW) effects. Within SAA, the EW anisotropy results in different level of exposure to each side of the ISS Zvezda SM, allowing angular evaluation of the anisotropic proton spectrum. While the combined magnitude of PA and EW effects at LEO depends on a multitude of factors such as trapped proton energy, orientation and altitude of the spacecraft along the velocity vector, this paper draws quantitative conclusions on the combined anisotropic magnitude differences within ISS SM target point between AP8 and AP9 models. Copyright © 2015 The Committee on Space Research (COSPAR). All rights reserved.

Engagement with the auditory processing system during targeted auditory cognitive training mediates changes in cognitive outcomes in individuals with schizophrenia

PubMed Central

Biagianti, Bruno; Fisher, Melissa; Neilands, Torsten B.; Loewy, Rachel; Vinogradov, Sophia

2016-01-01

BACKGROUND Individuals with schizophrenia who engage in targeted cognitive training (TCT) of the auditory system show generalized cognitive improvements. The high degree of variability in cognitive gains maybe due to individual differences in the level of engagement of the underlying neural system target. METHODS 131 individuals with schizophrenia underwent 40 hours of TCT. We identified target engagement of auditory system processing efficiency by modeling subject-specific trajectories of auditory processing speed (APS) over time. Lowess analysis, mixed models repeated measures analysis, and latent growth curve modeling were used to examine whether APS trajectories were moderated by age and illness duration, and mediated improvements in cognitive outcome measures. RESULTS We observed signifcant improvements in APS from baseline to 20 hours of training (initial change), followed by a flat APS trajectory (plateau) at subsequent time-points. Participants showed inter-individual variability in the steepness of the initial APS change and in the APS plateau achieved and sustained between 20–40 hours. We found that participants who achieved the fastest APS plateau, showed the greatest transfer effects to untrained cognitive domains. CONCLUSIONS There is a significant association between an individual's ability to generate and sustain auditory processing efficiency and their degree of cognitive improvement after TCT, independent of baseline neurocognition. APS plateau may therefore represent a behavioral measure of target engagement mediating treatment response. Future studies should examine the optimal plateau of auditory processing efficiency required to induce significant cognitive improvements, in the context of inter-individual differences in neural plasticity and sensory system efficiency that characterize schizophrenia. PMID:27617637

A paradoxical increase of a metabolite upon increased expression of its catabolic enzyme: the case of diadenosine tetraphosphate (Ap4A) and Ap4A phosphorylase I in Saccharomyces cerevisiae.

PubMed Central

Avila, D M; Robinson, A K; Kaushal, V; Barnes, L D

1991-01-01

The APA1 gene in Saccharomyces cerevisiae encodes Ap4A phosphorylase I, the catabolic enzyme for diadenosine 5',5"'-P1,P4-tetraphosphate (Ap4A). APA1 has been inserted into a multicopy plasmid and into a centromeric plasmid with a GAL1 promoter. Enhanced expression of APA1 via the plasmids resulted in 10- and 90-fold increases in Ap4A phosphorylase activity, respectively, as assayed in vitro. However, the intracellular concentration of Ap4A exhibited increases of 2- and 15-fold, respectively, from the two different plasmids. Intracellular Ap4A increased 3- to 20-fold during growth on galactose of a transformant with APA1 under the control of the GAL1 promoter. Intracellular adenosine 5'-P1-tetraphospho-P4-5"'-guanosine (Ap4G) and diguanosine 5',5"'-P1,P4-tetraphosphate (Gp4G) also increased in the transformant under these conditions. The chromosomal locus of APA1 has been disrupted in a haploid strain. The Ap4A phosphorylase activity decreased by 80% and the intracellular Ap4A concentration increased by a factor of five in the null mutant. These results with the null mutant agree with previous results reported by Plateau et al. (P. Plateau, M. Fromant, J.-M. Schmitter, J.-M. Buhler, and S. Blancquet, J. Bacteriol. 171:6437-6445, 1989). The paradoxical increase in Ap4A upon enhanced expression of APA1 indicates that the metabolic consequences of altered gene expression may be more complex than indicated solely by assay of enzymatic activity of the gene product. PMID:1660456

A paradoxical increase of a metabolite upon increased expression of its catabolic enzyme: the case of diadenosine tetraphosphate (Ap4A) and Ap4A phosphorylase I in Saccharomyces cerevisiae.

PubMed

Avila, D M; Robinson, A K; Kaushal, V; Barnes, L D

1991-12-01

The APA1 gene in Saccharomyces cerevisiae encodes Ap4A phosphorylase I, the catabolic enzyme for diadenosine 5',5"'-P1,P4-tetraphosphate (Ap4A). APA1 has been inserted into a multicopy plasmid and into a centromeric plasmid with a GAL1 promoter. Enhanced expression of APA1 via the plasmids resulted in 10- and 90-fold increases in Ap4A phosphorylase activity, respectively, as assayed in vitro. However, the intracellular concentration of Ap4A exhibited increases of 2- and 15-fold, respectively, from the two different plasmids. Intracellular Ap4A increased 3- to 20-fold during growth on galactose of a transformant with APA1 under the control of the GAL1 promoter. Intracellular adenosine 5'-P1-tetraphospho-P4-5"'-guanosine (Ap4G) and diguanosine 5',5"'-P1,P4-tetraphosphate (Gp4G) also increased in the transformant under these conditions. The chromosomal locus of APA1 has been disrupted in a haploid strain. The Ap4A phosphorylase activity decreased by 80% and the intracellular Ap4A concentration increased by a factor of five in the null mutant. These results with the null mutant agree with previous results reported by Plateau et al. (P. Plateau, M. Fromant, J.-M. Schmitter, J.-M. Buhler, and S. Blancquet, J. Bacteriol. 171:6437-6445, 1989). The paradoxical increase in Ap4A upon enhanced expression of APA1 indicates that the metabolic consequences of altered gene expression may be more complex than indicated solely by assay of enzymatic activity of the gene product.

Purification, characterisation and protective effects of polysaccharides from alfalfa on hepatocytes.

PubMed

Wang, Shaopu; Dong, Xiaofang; Ma, Hao; Cui, Yaoming; Tong, Jianming

2014-11-04

The objective of this study was to determine the preliminary characteristics and protective effects of alfalfa polysaccharides (APS) on hepatocytes in vitro. The crude APS was purified by DEAE-cellulose and Sephadex G-100 chromatography, resulting in the four purified fractions: APS-1, APS-2, APS-3 and APS-4. The results indicated that APS-3 had higher carbohydrate and uronic acid contents and that APS-4 had a more complicated monosaccharide composition compared to the other purified fractions. The average molecular weights of APS-1, APS-2, APS-3 and APS-4 were 48,536, 6,221, 66,559 and 13,076 Da, respectively. Furthermore, APS (crude and its purified fractions) restored the activities of antioxidant enzymes and increased the total antioxidant capacity of hepatocytes subjected to H2O2-induced oxidative stress. Furthermore, APS treatment counteracted the increases in lactic dehydrogenase and malonaldehyde in the culture supernatant. These results clearly demonstrate that APS possesses a protective effect against oxidative injury in hepatocytes. Copyright © 2014 Elsevier Ltd. All rights reserved.

Properties of an intermediate-duration inactivation process of the voltage-gated sodium conductance in rat hippocampal CA1 neurons.

PubMed

French, Christopher R; Zeng, Zhen; Williams, David A; Hill-Yardin, Elisa L; O'Brien, Terence J

2016-02-01

Rapid transmembrane flow of sodium ions produces the depolarizing phase of action potentials (APs) in most excitable tissue through voltage-gated sodium channels (NaV). Macroscopic currents display rapid activation followed by fast inactivation (IF) within milliseconds. Slow inactivation (IS) has been subsequently observed in several preparations including neuronal tissues. IS serves important physiological functions, but the kinetic properties are incompletely characterized, especially the operative timescales. Here we present evidence for an "intermediate inactivation" (II) process in rat hippocampal CA1 neurons with time constants of the order of 100 ms. The half-inactivation potentials (V0.5) of steady-state inactivation curves were hyperpolarized by increasing conditioning pulse duration from 50 to 500 ms and could be described by a sum of Boltzmann relations. II state transitions were observed after opening as well as subthreshold potentials. Entry into II after opening was relatively insensitive to membrane potential, and recovery of II became more rapid at hyperpolarized potentials. Removal of fast inactivation with cytoplasmic papaine revealed time constants of INa decay corresponding to II and IS with long depolarizations. Dynamic clamp revealed attenuation of trains of APs over the 10(2)-ms timescale, suggesting a functional role of II in repetitive firing accommodation. These experimental findings could be reproduced with a five-state Markov model. It is likely that II affects important aspects of hippocampal neuron response and may provide a drug target for sodium channel modulation. Copyright © 2016 the American Physiological Society.

Arrhythmic effects of Epac-mediated ryanodine receptor activation in Langendorff-perfused murine hearts are associated with reduced conduction velocity.

PubMed

Li, Mengye; Hothi, Sandeep S; Salvage, Samantha C; Jeevaratnam, Kamalan; Grace, Andrew A; Huang, Christopher L-H

2017-06-01

Recent papers have attributed arrhythmic substrate in murine RyR2-P2328S hearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct exchange protein directly activated by cAMP (Epac)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential (MAP) recordings demonstrated that initial steady (8 Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff-perfused wild-type mouse ventricles before pharmacological intervention. The Epac activator 8-CPT (8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate) (VT in 1 of 7 hearts), and the RyR2 blocker dantrolene, either alone (0 of 11) or with 8-CPT (0 of 9) did not then increase VT incidence (P>.05). Both progressively increased pacing rates and programmed extrasystolic (S2) stimuli similarly produced no VT in untreated hearts (n=20 and n=9 respectively). 8-CPT challenge then increased VT incidences (5 of 7 and 4 of 8 hearts respectively; P<.05). However, dantrolene, whether alone (0 of 10 and 1 of 13) or combined with 8-CPT (0 of 10 and 0 of 13) did not increase VT incidence relative to those observed in untreated hearts (P>.05). 8-CPT but not dantrolene, whether alone or combined with 8-CPT, correspondingly increased AP latencies (1.14±0.04 (n=7), 1.04±0.03 (n=10), 1.09±0.05 (n=8) relative to respective control values). In contrast, AP durations, conditions for 2:1 conduction block and ventricular effective refractory periods remained unchanged throughout. We thus demonstrate for the first time that acute RyR2 activation reversibly induces VT in specific association with reduced CV. © 2017 The Authors. Clinical and Experimental Pharmacology and Physiology Published by John Wiley & Sons Australia, Ltd.

Influence of N-alkylation on organ distribution of radioiodinated amphetamines

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

Machulla, H.J.; Schmidt, U.; Mehdorn, H.M.

1985-05-01

In spite of numerous animal data and the widespread clinical application of p-(I-123)-N-isopropyl-amphetamine, questions remain open about the role of N-alkylation. Therefore, amphetamine (AP), N-methyl- (MeAP), and N-isopropyl-amphetamine (IsAP) were radioiodinated in the para position and the organ distribution was determined in male mice (Freiburg tribe) 10 weeks of age. In the lungs, all derivatives showed principally the same kinetics. In brain, the maximum uptake was reached after 30 min with 12%/g for AP and MeAP, and 10.5%/g for IsAP. In liver, the radioactivity similarly increased during the first 15 min to approx. 12%/g; afterwards, AP clearly decreased but MeAPmore » remained almost constant up to 120 min and, even more, IsAP increased to a maximum of 18%/g at 30 min. The same brain uptake kinetics for all 3 substances exclude the importance of lipophilicity increased by the N-alkylation. Furthermore, the differences in the liver kinetics of AP and both MeAP and IsAP indicate the importance of liver metabolism on the alkylated amphetamines. The results support the hypothesis that the first important metabolite of the N-alkylated derivatives is the amphetamine which accumulates in the brain as do MeAP and IsAP. On the basis of these findings, AP was applied clinically showing the same efficient brain uptake and distribution in SPECT as IsAP.« less

Differential calcium sensitivity in NaV 1.5 mixed syndrome mutants.

PubMed

Abdelsayed, Mena; Baruteau, Alban-Elouen; Gibbs, Karen; Sanatani, Shubhayan; Krahn, Andrew D; Probst, Vincent; Ruben, Peter C

2017-09-15

SCN5a mutations may express gain-of-function (Long QT Syndrome-3), loss-of-function (Brugada Syndrome 1) or both (mixed syndromes), depending on the mutation and environmental triggers. One such trigger may be an increase in cytosolic calcium, accompanying exercise. Many mixed syndromes mutants, including ∆KPQ, E1784K, 1795insD and Q1909R, are found in calcium-sensitive regions. Elevated cytosolic calcium attenuates gain-of-function properties in ∆KPQ, 1795insD and Q1909R, but not in E1784K. By contrast, elevated cytosolic calcium further exacerbates gain-of-function in E1784K by destabilizing slow inactivation. Action potential modelling, using a modified O'Hara Rudy model, suggests that elevated heart rate rescues action potential duration in ∆KPQ, 1795insD and Q1909R, but not in E1784K. Action potential simulations suggest that E1784K carriers have an increased intracellular sodium-to-calcium ratio under bradycardia and tachycardia conditions. Elevated cytosolic calcium, which is common during high heart rates, ameliorates or exacerbates the mixed syndrome phenotype depending on the genetic signature. Inherited arrhythmias may arise from mutations in the gene for SCN5a, which encodes the cardiac voltage-gated sodium channel, Na V 1.5. Mutants in Na V 1.5 result in Brugada Syndrome (BrS1), Long-QT Syndrome (LQT3) or mixed syndromes (an overlap of BrS1/LQT3). Exercise is a potential arrhythmogenic trigger in mixed syndromes. We aimed to determine the effects of elevated cytosolic calcium, which is common during exercise, in mixed syndrome Na V 1.5 mutants. We used whole-cell patch clamp to assess the biophysical properties of Na V 1.5 wild-type (WT), ∆KPQ, E1784K, 1795insD and Q1909R mutants in human embryonic kidney 293 cells transiently transfected with the Na V 1.5 α subunit (WT or mutants), β1 subunit and enhanced green fluorescent protein. Voltage-dependence and kinetics were measured at cytosolic calcium levels of approximately 0, 500 and 2500 nm. In silico, action potential (AP) model simulations were performed using a modified O'Hara Rudy model. Elevated cytosolic calcium attenuates the late sodium current in ∆KPQ, 1795insD and Q1909R, but not in E1784K. Elevated cytosolic calcium restores steady-state slow inactivation (SSSI) to the WT-form in Q1909R, but depolarized SSSI in E1784K. Our AP simulations showed a frequency-dependent reduction of AP duration in ∆KPQ, 1795insD and Q1909R carriers. In E1784K, AP duration is relatively prolonged at both low and high heart rates, resulting in a sodium overload. Cellular perturbations during exercise may affect BrS1/LQT3 patients differently depending on their individual genetic signature. Thus, exercise may be therapeutic or may be an arrhythmogenic trigger in some SCN5a patients. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Engagement with the auditory processing system during targeted auditory cognitive training mediates changes in cognitive outcomes in individuals with schizophrenia.

PubMed

Biagianti, Bruno; Fisher, Melissa; Neilands, Torsten B; Loewy, Rachel; Vinogradov, Sophia

2016-11-01

Individuals with schizophrenia who engage in targeted cognitive training (TCT) of the auditory system show generalized cognitive improvements. The high degree of variability in cognitive gains maybe due to individual differences in the level of engagement of the underlying neural system target. 131 individuals with schizophrenia underwent 40 hours of TCT. We identified target engagement of auditory system processing efficiency by modeling subject-specific trajectories of auditory processing speed (APS) over time. Lowess analysis, mixed models repeated measures analysis, and latent growth curve modeling were used to examine whether APS trajectories were moderated by age and illness duration, and mediated improvements in cognitive outcome measures. We observed significant improvements in APS from baseline to 20 hours of training (initial change), followed by a flat APS trajectory (plateau) at subsequent time-points. Participants showed interindividual variability in the steepness of the initial APS change and in the APS plateau achieved and sustained between 20 and 40 hours. We found that participants who achieved the fastest APS plateau, showed the greatest transfer effects to untrained cognitive domains. There is a significant association between an individual's ability to generate and sustain auditory processing efficiency and their degree of cognitive improvement after TCT, independent of baseline neurocognition. APS plateau may therefore represent a behavioral measure of target engagement mediating treatment response. Future studies should examine the optimal plateau of auditory processing efficiency required to induce significant cognitive improvements, in the context of interindividual differences in neural plasticity and sensory system efficiency that characterize schizophrenia. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

The 4-aminopyridine in vitro epilepsy model analyzed with a perforated multi-electrode array.

PubMed

Gonzalez-Sulser, Alfredo; Wang, Jing; Motamedi, Gholam K; Avoli, Massimo; Vicini, Stefano; Dzakpasu, Rhonda

2011-06-01

Epileptiform discharges recorded in the 4-aminopyridine (4-AP) in vitro epilepsy model are mediated by glutamatergic and GABAergic signaling. Using a 60-channel perforated multi-electrode array (pMEA) on corticohippocampal slices from 2 to 3 week old mice we recorded interictal- and ictal-like events. When glutamatergic transmission was blocked, interictal-like events no longer initiated in the hilus or CA3/CA1 pyramidal layers but originated from the dentate gyrus granule and molecular layers. Furthermore, frequencies of interictal-like events were reduced and durations were increased in these regions while cortical discharges were completely blocked. Following GABA(A) receptor blockade interictal-like events no longer propagated to the dentate gyrus while their frequency in CA3 increased; in addition, ictal-like cortical events became shorter while increasing in frequency. Lastly, drugs that affect tonic and synaptic GABAergic conductance modulated the frequency, duration, initiation and propagation of interictal-like events. These findings confirm and expand on previous studies indicating that multiple synaptic mechanisms contribute to synchronize neuronal network activity in forebrain structures. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. Copyright © 2010 Elsevier Ltd. All rights reserved.

Incidence and nature of adverse reactions to antibiotics used as endocarditis prophylaxis

PubMed Central

Thornhill, Martin H.; Dayer, Mark J.; Prendergast, Bernard; Baddour, Larry M.; Jones, Simon; Lockhart, Peter B.

2015-01-01

Objectives Antibiotic prophylaxis (AP) administration prior to invasive dental procedures has been a leading focus of infective endocarditis prevention. However, there have been long-standing concerns about the risk of adverse drug reactions as a result of this practice. The objective of this study was to identify the incidence and nature of adverse reactions to amoxicillin and clindamycin prophylaxis to prevent infective endocarditis. Methods We obtained AP prescribing data for England from January 2004 to March 2014 from the NHS Business Services Authority, and adverse drug reaction data from the Medicines and Healthcare Products Regulatory Agency's Yellow Card reporting scheme for prescriptions of the standard AP protocol of a single 3 g oral dose of amoxicillin or a single 600 mg oral dose of clindamycin for those allergic to penicillin. Results The reported adverse drug reaction rate for amoxicillin AP was 0 fatal reactions/million prescriptions (in fact 0 fatal reactions for nearly 3 million prescriptions) and 22.62 non-fatal reactions/million prescriptions. For clindamycin, it was 13 fatal and 149 non-fatal reactions/million prescriptions. Most clindamycin adverse drug reactions were Clostridium difficile infections. Conclusions AP adverse drug reaction reporting rates in England were low, particularly for amoxicillin, and lower than previous estimates. This suggests that amoxicillin AP is comparatively safe for patients without a history of amoxicillin allergy. The use of clindamycin AP was, however, associated with significant rates of fatal and non-fatal adverse drug reactions associated with C. difficile infections. These were higher than expected and similar to those for other doses, durations and routes of clindamycin administration. PMID:25925595

Prediction of hypertensive crisis based on average, variability and approximate entropy of 24-h ambulatory blood pressure monitoring.

PubMed

Schoenenberger, A W; Erne, P; Ammann, S; Perrig, M; Bürgi, U; Stuck, A E

2008-01-01

Approximate entropy (ApEn) of blood pressure (BP) can be easily measured based on software analysing 24-h ambulatory BP monitoring (ABPM), but the clinical value of this measure is unknown. In a prospective study we investigated whether ApEn of BP predicts, in addition to average and variability of BP, the risk of hypertensive crisis. In 57 patients with known hypertension we measured ApEn, average and variability of systolic and diastolic BP based on 24-h ABPM. Eight of these fifty-seven patients developed hypertensive crisis during follow-up (mean follow-up duration 726 days). In bivariate regression analysis, ApEn of systolic BP (P<0.01), average of systolic BP (P=0.02) and average of diastolic BP (P=0.03) were significant predictors of hypertensive crisis. The incidence rate ratio of hypertensive crisis was 14.0 (95% confidence interval (CI) 1.8, 631.5; P<0.01) for high ApEn of systolic BP as compared to low values. In multivariable regression analysis, ApEn of systolic (P=0.01) and average of diastolic BP (P<0.01) were independent predictors of hypertensive crisis. A combination of these two measures had a positive predictive value of 75%, and a negative predictive value of 91%, respectively. ApEn, combined with other measures of 24-h ABPM, is a potentially powerful predictor of hypertensive crisis. If confirmed in independent samples, these findings have major clinical implications since measures predicting the risk of hypertensive crisis define patients requiring intensive follow-up and intensified therapy.

SPAK kinase is a substrate and target of PKCθ in T-cell receptor-induced AP-1 activation pathway

PubMed Central

Li, Yingqiu; Hu, Junru; Vita, Randi; Sun, Binggang; Tabata, Hiroki; Altman, Amnon

2004-01-01

Protein kinase C-θ (PKCθ) plays an important role in T-cell activation via stimulation of AP-1 and NF-κB. Here we report the isolation of SPAK, a Ste20-related upstream mitogen-activated protein kinase (MAPK), as a PKCθ-interacting kinase. SPAK interacted with PKCθ (but not with PKCα) via its 99 COOH-terminal residues. TCR/CD28 costimulation enhanced this association and stimulated the catalytic activity of SPAK. Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCθ, but not by PKCα. The magnitude and duration of TCR/CD28-induced endogenous SPAK activation were markedly impaired in PKCθ-deficient T cells. Transfected SPAK synergized with constitutively active PKCθ to activate AP-1, but not NF-κB. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCθ-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK. Conversely, a SPAK-specific RNAi or a dominant-negative SPAK mutant inhibited PKCθ- and TCR/CD28-induced AP-1, but not NF-κB, activation. These results define SPAK as a substrate and target of PKCθ in a TCR/CD28-induced signaling pathway leading selectively to AP-1 (but not NF-κB) activation. PMID:14988727

Classification of Physical Activity: Information to Artificial Pancreas Control Systems in Real Time.

PubMed

Turksoy, Kamuran; Paulino, Thiago Marques Luz; Zaharieva, Dessi P; Yavelberg, Loren; Jamnik, Veronica; Riddell, Michael C; Cinar, Ali

2015-10-06

Physical activity has a wide range of effects on glucose concentrations in type 1 diabetes (T1D) depending on the type (ie, aerobic, anaerobic, mixed) and duration of activity performed. This variability in glucose responses to physical activity makes the development of artificial pancreas (AP) systems challenging. Automatic detection of exercise type and intensity, and its classification as aerobic or anaerobic would provide valuable information to AP control algorithms. This can be achieved by using a multivariable AP approach where biometric variables are measured and reported to the AP at high frequency. We developed a classification system that identifies, in real time, the exercise intensity and its reliance on aerobic or anaerobic metabolism and tested this approach using clinical data collected from 5 persons with T1D and 3 individuals without T1D in a controlled laboratory setting using a variety of common types of physical activity. The classifier had an average sensitivity of 98.7% for physiological data collected over a range of exercise modalities and intensities in these subjects. The classifier will be added as a new module to the integrated multivariable adaptive AP system to enable the detection of aerobic and anaerobic exercise for enhancing the accuracy of insulin infusion strategies during and after exercise. © 2015 Diabetes Technology Society.

Treatment of Thrombotic Antiphospholipid Syndrome: The Rationale of Current Management—An Insight into Future Approaches

PubMed Central

Ubiali, Tania; Meroni, Pier Luigi

2015-01-01

Vascular thrombosis and pregnancy morbidity represent the clinical manifestations of antiphospholipid syndrome (APS), which is serologically characterized by the persistent positivity of antiphospholipid antibodies (aPL). Antiplatelet and anticoagulant agents currently provide the mainstay of APS treatment. However, the debate is still open: controversies involve the intensity and the duration of anticoagulation and the treatment of stroke and refractory cases. Unfortunately, the literature cannot provide definite answers to these controversial issues as it is flawed by many limitations, mainly due to the recruitment of patients not fulfilling laboratory and clinical criteria for APS. The recommended therapeutic management of different aPL-related clinical manifestations is hereby presented, with a critical appraisal of the evidence supporting such approaches. Cutting edge therapeutic strategies are also discussed, presenting the pioneer reports about the efficacy of novel pharmacological agents in APS. Thanks to a better understanding of aPL pathogenic mechanisms, new therapeutic targets will soon be explored. Much work is still to be done to unravel the most controversial issues about APS management: future studies are warranted to define the optimal management according to aPL risk profile and to assess the impact of a strict control of cardiovascular risk factors on disease control. PMID:26075289

Classification of Physical Activity

PubMed Central

Turksoy, Kamuran; Paulino, Thiago Marques Luz; Zaharieva, Dessi P.; Yavelberg, Loren; Jamnik, Veronica; Riddell, Michael C.; Cinar, Ali

2015-01-01

Physical activity has a wide range of effects on glucose concentrations in type 1 diabetes (T1D) depending on the type (ie, aerobic, anaerobic, mixed) and duration of activity performed. This variability in glucose responses to physical activity makes the development of artificial pancreas (AP) systems challenging. Automatic detection of exercise type and intensity, and its classification as aerobic or anaerobic would provide valuable information to AP control algorithms. This can be achieved by using a multivariable AP approach where biometric variables are measured and reported to the AP at high frequency. We developed a classification system that identifies, in real time, the exercise intensity and its reliance on aerobic or anaerobic metabolism and tested this approach using clinical data collected from 5 persons with T1D and 3 individuals without T1D in a controlled laboratory setting using a variety of common types of physical activity. The classifier had an average sensitivity of 98.7% for physiological data collected over a range of exercise modalities and intensities in these subjects. The classifier will be added as a new module to the integrated multivariable adaptive AP system to enable the detection of aerobic and anaerobic exercise for enhancing the accuracy of insulin infusion strategies during and after exercise. PMID:26443291

Human ex-vivo action potential model for pro-arrhythmia risk assessment.

PubMed

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.

Modulation of KCNQ1 alternative splicing regulates cardiac IKs and action potential repolarization.

PubMed

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.

Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis

PubMed Central

Wu, Qi; Henry, James L

2009-01-01

Background Clinical data on osteoarthritis (OA) suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naïve control animals. Pilot data indicated no difference in C- or Aδ-fiber associated neurons and therefore the focus is on Aβ-fiber nociceptive neurons. Results At one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Aβ-fiber dorsal root ganglion (DRG) neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Aβ-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis. Conclusion These data indicate that Aβ nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Aβ-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA. PMID:19785765

Human ex-vivo action potential model for pro-arrhythmia risk assessment

PubMed Central

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

Dissecting Costs of CT Study: Application of TDABC (Time-driven Activity-based Costing) in a Tertiary Academic Center.

PubMed

Anzai, Yoshimi; Heilbrun, Marta E; Haas, Derek; Boi, Luca; Moshre, Kirk; Minoshima, Satoshi; Kaplan, Robert; Lee, Vivian S

2017-02-01

The lack of understanding of the real costs (not charge) of delivering healthcare services poses tremendous challenges in the containment of healthcare costs. In this study, we applied an established cost accounting method, the time-driven activity-based costing (TDABC), to assess the costs of performing an abdomen and pelvis computed tomography (AP CT) in an academic radiology department and identified opportunities for improved efficiency in the delivery of this service. The study was exempt from an institutional review board approval. TDABC utilizes process mapping tools from industrial engineering and activity-based costing. The process map outlines every step of discrete activity and duration of use of clinical resources, personnel, and equipment. By multiplying the cost per unit of capacity by the required task time for each step, and summing each component cost, the overall costs of AP CT is determined for patients in three settings, inpatient (IP), outpatient (OP), and emergency departments (ED). The component costs to deliver an AP CT study were as follows: radiologist interpretation: 40.1%; other personnel (scheduler, technologist, nurse, pharmacist, and transporter): 39.6%; materials: 13.9%; and space and equipment: 6.4%. The cost of performing CT was 13% higher for ED patients and 31% higher for inpatients (IP), as compared to that for OP. The difference in cost was mostly due to non-radiologist personnel costs. Approximately 80% of the direct costs of AP CT to the academic medical center are related to labor. Potential opportunities to reduce the costs include increasing the efficiency of utilization of CT, substituting lower cost resources when appropriate, and streamlining the ordering system to clarify medical necessity and clinical indications. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

Calcium transient dynamics and the mechanisms of ventricular vulnerability to single premature electrical stimulation in Langendorff-perfused rabbit ventricles

PubMed Central

Hayashi, Hideki; Kamanu, Santosh Dora; Ono, Norihiko; Kawase, Ayaka; Chou, Chung-Chuan; Weiss, James N.; Karagueuzian, Hrayr S.; Lin, Shien-Fong; Chen, Peng-Sheng

2009-01-01

BACKGROUND Single strong premature electrical stimulation (S2) may induce figure-eight reentry. We hypothesize that Ca current-mediated slow-response action potentials (APs) play a key role in the propagation in the central common pathway (CCP) of the reentry. METHODS We simultaneously mapped optical membrane potential (Vm) and intracellular Ca (Cai) transients in isolated Langendorff-perfused rabbit ventricles. Baseline pacing (S1) and a cathodal S2 (40 – 80 mA) were given at different epicardial sites with a coupling interval of 135 ± 20 ms. RESULTS In all 6 hearts, S2 induced graded responses around the S2 site. These graded responses propagated locally toward the S1 site and initiated fast APs from recovered tissues. The wavefront then circled around the refractory tissue near the site of S2. At the side of S2 opposite to the S1, the graded responses prolonged AP duration while the Cai continued to decline, resulting in a Cai sinkhole (an area of low Cai). The Cai in the sinkhole then spontaneously increased, followed by a slow Vm depolarization with a take-off potential of −40 ± 3.9 mV, which was confirmed with microelectrode recordings in 3 hearts. These slow-response APs then propagated through CCP to complete a figure-eight reentry. CONCLUSION We conclude that a strong premature stimulus can induce a Cai sinkhole at the entrance of the CCP. Spontaneous Cai elevation in the Cai sinkhole precedes the Vm depolarization, leading to Ca current-mediated slow propagation in the CCP. The slow propagation allows more time for tissues at the other side of CCP to recover and be excited to complete figure-eight reentry. PMID:18180025

Calcium transient dynamics and the mechanisms of ventricular vulnerability to single premature electrical stimulation in Langendorff-perfused rabbit ventricles.

PubMed

Hayashi, Hideki; Kamanu, Santosh Dora; Ono, Norihiko; Kawase, Ayaka; Chou, Chung-Chuan; Weiss, James N; Karagueuzian, Hrayr S; Lin, Shien-Fong; Chen, Peng-Sheng

2008-01-01

Single strong premature electrical stimulation (S(2)) may induce figure-eight reentry. We hypothesize that Ca current-mediated slow-response action potentials (APs) play a key role in the propagation in the central common pathway (CCP) of the reentry. We simultaneously mapped optical membrane potential (V(m)) and intracellular Ca (Ca(i)) transients in isolated Langendorff-perfused rabbit ventricles. Baseline pacing (S(1)) and a cathodal S(2) (40-80 mA) were given at different epicardial sites with a coupling interval of 135 +/- 20 ms. In all 6 hearts, S(2) induced graded responses around the S(2) site. These graded responses propagated locally toward the S(1) site and initiated fast APs from recovered tissues. The wavefront then circled around the refractory tissue near the site of S(2). At the side of S(2) opposite to the S(1), the graded responses prolonged AP duration while the Ca(i) continued to decline, resulting in a Ca(i) sinkhole (an area of low Ca(i)). The Ca(i) in the sinkhole then spontaneously increased, followed by a slow V(m) depolarization with a take-off potential of -40 +/- 3.9 mV, which was confirmed with microelectrode recordings in 3 hearts. These slow-response APs then propagated through CCP to complete a figure-eight reentry. We conclude that a strong premature stimulus can induce a Ca(i) sinkhole at the entrance of the CCP. Spontaneous Ca(i) elevation in the Ca(i) sinkhole precedes the V(m) depolarization, leading to Ca current-mediated slow propagation in the CCP. The slow propagation allows more time for tissues at the other side of CCP to recover and be excited to complete figure-eight reentry.

Gender, Academics and Interscholastic Sports Participation at the School Level: A Gender-specific Analysis of the Relationship between Interscholastic Sports Participation and AP Enrollment

PubMed Central

Veliz, Philip; Shakib, Sohaila

2014-01-01

While literature demonstrates that interscholastic sports participation is associated with positive academic outcomes, this relationship is rarely analyzed at a macro-level (the school-level). To date, there is no research examining whether increases in schools’ female and male interscholastic sports participation rates is associated with increases in female and male AP enrollment rates. Using a national sample of 4,644 public high schools during the 2009-2010 school year, we test several gender-specific hypotheses linked with the association between schools’ sport participation rates and advanced placement enrollment rates (AP math, AP science, AP foreign language, and overall AP enrollment). The findings reveal that schools’ female and male sports participation rates have a positive association with schools’ female and male AP math, AP science, AP foreign language, and overall AP enrollment rates. Moreover, the findings suggest that females benefit more than males in regard to the positive relationship between interscholastic sports and AP enrollment. PMID:24910475

Diadenosine 5', 5'''-P(1),P(4)-tetraphosphate (Ap4A) is synthesized in response to DNA damage and inhibits the initiation of DNA replication.

PubMed

Marriott, Andrew S; Copeland, Nikki A; Cunningham, Ryan; Wilkinson, Mark C; McLennan, Alexander G; Jones, Nigel J

2015-09-01

The level of intracellular diadenosine 5', 5'''-P(1),P(4)-tetraphosphate (Ap4A) increases several fold in mammalian cells treated with non-cytotoxic doses of interstrand DNA-crosslinking agents such as mitomycin C. It is also increased in cells lacking DNA repair proteins including XRCC1, PARP1, APTX and FANCG, while >50-fold increases (up to around 25 μM) are achieved in repair mutants exposed to mitomycin C. Part of this induced Ap4A is converted into novel derivatives, identified as mono- and di-ADP-ribosylated Ap4A. Gene knockout experiments suggest that DNA ligase III is primarily responsible for the synthesis of damage-induced Ap4A and that PARP1 and PARP2 can both catalyze its ADP-ribosylation. Degradative proteins such as aprataxin may also contribute to the increase. Using a cell-free replication system, Ap4A was found to cause a marked inhibition of the initiation of DNA replicons, while elongation was unaffected. Maximum inhibition of 70-80% was achieved with 20 μM Ap4A. Ap3A, Ap5A, Gp4G and ADP-ribosylated Ap4A were without effect. It is proposed that Ap4A acts as an important inducible ligand in the DNA damage response to prevent the replication of damaged DNA. Copyright © 2015 Elsevier B.V. All rights reserved.

Mannose-coated gadolinium liposomes for improved magnetic resonance imaging in acute pancreatitis.

PubMed

Tian, Bing; Liu, Ri; Chen, Shiyue; Chen, Luguang; Liu, Fang; Jia, Guorong; Dong, Yinmei; Li, Jing; Chen, Huaiwen; Lu, Jianping

2017-01-01

Acute pancreatitis (AP) is an acute inflammatory condition of the pancreas. The symptoms, treatment, and prognosis of mild and severe AP are different, and severe AP is a potentially life-threatening disease with a high incidence of complications and high mortality rate. Thus, it is urgent to develop an effective approach to reliably discriminate between mild and severe AP. We have developed novel gadolinium-diethylenetriaminepentaacetic (Gd-DTPA)-loaded mannosylated liposomes (named thereafter M-Gd-NL) that preferably target macrophages in AP. The targeting ability of M-Gd-NL toward macrophages in AP and its ability to discriminate between mild and severe AP were evaluated. The liposomes were of desired particle size (~100 nm), Gd-DTPA encapsulation efficiency (~85%), and stability. M-Gd-NL and non-targeted Gd-DTPA-loaded liposomes (Gd-NL) exhibited increased relaxivity compared with Gd-DTPA. Compared with Gd-NL and Gd-DTPA, M-Gd-NL showed increased uptake in macrophages, resulting in increased T 1 imaging ability both in vitro (macrophage cell line) and in vivo (severe AP model). Importantly, M-Gd-NL had the ability to discriminate between mild and severe AP, as reflected by a significantly higher T 1 magnetic resonance imaging signal in severe AP than in mild AP. M-Gd-NL did not show severe organ toxicity in rats. Our data suggest that M-Gd-NL had enhanced magnetic resonance imaging ability by targeting macrophages in AP and good ability to discriminate between mild and severe AP. We believe that M-Gd-NL could shed new light on the diagnosis of AP in the near future.

Elevated increases in human-perceived temperature under climate warming

NASA Astrophysics Data System (ADS)

Li, Jianfeng; Chen, Yongqin David; Gan, Thian Yew; Lau, Ngar-Cheung

2018-01-01

Changes in air temperature (AT), humidity and wind speed (Wind) affect apparent temperature (AP), the human-perceived equivalent temperature1-3. Here we show that under climate warming, both reanalysis data sets and Global Climate Model simulations indicate that AP has increased faster than AT over land. The faster increase in AP has been especially significant over low latitudes and is expected to continue in the future. The global land average AP increased at 0.04 °C per decade faster than AT before 2005. This trend is projected to increase to 0.06 °C (0.03-0.09 °C; minimum and maximum of the ensemble members) per decade and 0.17 °C (0.12-0.25 °C) per decade under the Representative Concentration Pathway 4.5 scenario (RCP4.5) and RCP8.5, respectively, and reduce to 0.02 °C (0-0.03 °C) per decade under RCP2.6 over 2006-2100. The higher increment in AP in summer daytime is more remarkable than in winter night-time and is most prominent over low latitudes. The summertime increases in AT-based thermal discomfort are projected to balance the wintertime decreases in AT-based discomfort over low and middle latitudes, while the summertime increases in AP-based thermal discomfort are expected to outpace the wintertime decreases in AP-based thermal discomfort. Effective climate change mitigation efforts to achieve RCP2.6 can considerably alleviate the faster increase in AP.

Enhanced effect of VEGF165 on L-type calcium currents in guinea-pig cardiac ventricular myocytes.

PubMed

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.

Glaucoma patients present increased levels of diadenosine tetraphosphate, Ap(4)A, in the aqueous humour.

PubMed

Castany, Marta; Jordi, Isabel; Catala, Jaume; Gual, Arcadi; Morales, Miguel; Gasull, Xavier; Pintor, Jesus

2011-03-01

Previous studies have shown the presence of diadenosine tetraphosphate (Ap(4)A) and pentaphosphate (Ap(5)A) in the aqueous humour (AH) of different species. When topically applied to the rabbit cornea, Ap(4)A decreased IOP while Ap(5)A increased it. Here we study the presence of dinucleoside polyphosphates in the AH from human patients with or without glaucoma. AH was obtained at the time of cataract surgery from patients with (n=16) or without (n=10) primary open-angle glaucoma. AH (0.1-0.2 ml) was collected at the beginning of surgery through a corneal paracentesis and immediately cooled in liquid nitrogen, kept frozen and protected from light. AH aliquots were analyzed by HPLC for the presence of Ap(4)A and Ap(5)A. Both, Ap(4)A and Ap(5)A were detected in the AH of both experimental groups. No significant differences were found for Ap(5)A. In contrast, Ap(4)A levels were increased by ∼15-fold in the AH from glaucomatous eyes ranging from 19.5±9.2 nM in normal individuals to 286.03±30.9 nM in glaucomatous patients. In conclusion, both Ap(4)A and Ap(5)A were detected for the first time in human AH. Interestingly, glaucomatous eyes presented elevated concentrations of Ap(4)A compared to controls. The role of Ap(4)A needs to be elucidated but it may help to protect the autonomic innervation in the ciliary body/trabecular meshwork. Also, because of its higher levels in glaucoma patients it may be considered as a possible glaucoma biomarker. Copyright © 2010 Elsevier Ltd. All rights reserved.

Rosiglitazone Improves Survival and Hastens Recovery from Pancreatic Inflammation in Obese Mice

PubMed Central

Pini, Maria; Rhodes, Davina H.; Castellanos, Karla J.; Cabay, Robert J.; Grady, Eileen F.; Fantuzzi, Giamila

2012-01-01

Obesity increases severity of acute pancreatitis (AP) by unclear mechanisms. We investigated the effect of the PPAR-gamma agonist rosiglitazone (RGZ, 0.01% in the diet) on severity of AP induced by administration of IL-12+ IL-18 in male C57BL6 mice fed a low fat (LFD) or high fat diet (HFD), under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals. In both LFD and HFD mice without AP, RGZ significantly increased body weight and % fat mass, with significant upregulation of adiponectin and suppression of erythropoiesis. In HFD mice with AP, RGZ significantly increased survival and hastened recovery from pancreatic inflammation, as evaluated by significantly improved pancreatic histology, reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP. This was associated with significantly lower circulating and pancreas-associated levels of IL-6, Galectin-3, osteopontin and TIMP-1 in HFD + RGZ mice, particularly at Day 7 post-AP. In LFD mice with AP, RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification, without affecting other parameters of disease severity or inflammation. Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice. In conclusion, RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity, indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu. However, RGZ worsens selective parameters of AP severity in LFD mice. PMID:22815875

Robust Humoral and Cellular Immune Responses to Pertussis in Adults After a First Acellular Booster Vaccination.

PubMed

van der Lee, Saskia; van Rooijen, Debbie M; de Zeeuw-Brouwer, Mary-Lène; Bogaard, Marjan J M; van Gageldonk, Pieter G M; Marinovic, Axel Bonacic; Sanders, Elisabeth A M; Berbers, Guy A M; Buisman, Anne-Marie

2018-01-01

To reduce the pertussis disease burden, nowadays several countries recommend acellular pertussis (aP) booster vaccinations for adults. We aimed to evaluate the immunogenicity of a first adult aP booster vaccination at childbearing age. In 2014, healthy adults aged 25-29 years ( n  = 105), vaccinated during infancy with four doses of whole-cell pertussis (wP) vaccine, received a Tdap (tetanus, diphtheria, and aP) booster vaccination. Blood samples were collected longitudinally pre-booster, 2 and 4 weeks, and 1 year and 2 years post-booster. Tdap vaccine antigen-specific antibody levels and memory B- and T-cell responses were determined at all time points. Antibody persistence was calculated using a bi-exponential decay model. Upon booster vaccination, the IgG levels specific to all Tdap vaccine antigens were significantly increased. After an initial rapid decline in the first year, PT-IgG antibody decay was limited (15%) in the second year post-booster. The duration of a median level of PT-IgG ≥20 IU/mL was estimated to be approximately 9 years. Vaccine antigen-specific memory B- and T-cell numbers increased and remained at high levels although a significant decline was observed after 4 weeks post-booster. However, Th1, Th2, and Th17 cytokine production remained above pre-booster levels for 2 years. The Tdap booster vaccination in wP-primed Dutch adults induced robust long-term humoral and cellular immune responses to pertussis antigens. Furthermore, PT-IgG levels are predicted to remain above the presumed protective cut-off for at least 9 years which might deserves further attention in evaluating the current recommendation to revaccinate women during every new pregnancy.

Fast radio bursts and their possible neutron star origins

NASA Astrophysics Data System (ADS)

Hessels, J. W. T.

2017-12-01

The discovery of the ‘Lorimer Burst’, a little over a decade ago, ignited renewed interest in searching for short-duration radio transients (Lorimer et al 2007 Science 318 777). This event is now considered to be the first established Fast Radio Burst (FRB), which is a class of millisecond-duration radio transients (Thornton et al 2013 Science 341 53). The large dispersive delays observed in FRBs distinguish them from the individual bright pulses from Galactic pulsars, and suggests that they originate deep in extragalactic space. Amazingly, FRBs are not rare: the implied event rate ranges up to many thousands of events per sky, per day (Champion et al 2016 MNRAS 460 L30). The fact that only two dozen FRBs have been discovered to date is a consequence of the limited sensitivity and field of view of current radio telescopes (Petroff et al 2016 PASA 33 e045). The precise localization of FRB 121102, the first and currently only FRB observed to repeat (Spitler et al 2014 ApJ 790 101; Spitler et al 2016 Nature 531 202; Scholz et al 2016 ApJ 833 177), has led to the unambiguous identification of its host galaxy and thus proven its extragalactic origin and large energy scale (Chatterjee et al 2017 Nature 541 58; Tendulkar et al 2017 ApJL 834 L7; Marcote et al 2017 ApJL 834 L8). It remains unclear, however, whether all FRBs are capable of repeating [many appear far less active (Petroff et al 2015 MNRAS 454 457)] or whether FRB 121102 implies that there are multiple sub-classes. Regardless, the repetitive nature of FRB 121102 and its localization to within a star-forming region in the host galaxy (Bassa et al 2017 ApJL 843 L8) imply that the bursts might originate from an exceptionally powerful neutron star - one necessarily quite unlike any we have observed in the Milky Way. In these proceedings, I give a very brief introduction to the FRB phenomenon and focus primarily on the insights that FRB 121102 has provided thus far.

Diadenosine polyphosphates Ap3A and Ap4A, but not Ap5A or Ap6A, induce proliferation of vascular smooth muscle cells.

PubMed

Bobbert, Peter; Schlüter, Hartmut; Schultheiss, Heinz Peter; Reusch, Hans Peter

2008-05-15

Depending on the number of phosphate groups, diadenosine polyphosphates (ApnA, Ap3A, Ap4A, Ap5A and Ap6A) differ in properties such as proliferation, apoptosis, vasoconstriction and vasodilatation of vascular smooth muscle cells (VSMCs). Possible signaling pathways leading to effects such as proliferation are still unknown. This study examined the proliferative effects of diadenosine polyphosphates on VSMCs and their intracellular pathways. Proliferation of VSMCs was measured by the cell count and [(3)H] thymidine incorporation. Phosphorylation of the MAP kinases ERK1/2 was determined by Western blotting. Single-cell [Ca(2+)](i) measurements were done to determine the influence of [Ca(2+)](i) on intracellular signaling. Stress fiber formation was assessed by fluorescence microscopy to detect an influence of G alpha(12). Ap3A and Ap4A, but not Ap5A or Ap6A, were shown to increase proliferation of VSMCs by activating P2Y receptors, which leads to stimulation of the Ras-Raf-MEK-ERK1/2 cascade. Ap3A- and Ap4A-induced activation of the MAP kinases ERK1/2 was dependent on a signaling pathway that included the EGF receptor, PKC, PLCbeta and the increase of [Ca(2+)](i). In conclusion, Ap3A and Ap4A, but not Ap5A or Ap6A, induce proliferation of VSMCs by a signaling pathway that begins with activation of P2Y receptors and leads to stimulation of the MAP kinases ERK1/2.

A Multiple Indicators Multiple Causes (MIMIC) model of internal barriers to drug treatment in China.

PubMed

Qi, Chang; Kelly, Brian C; Liao, Yanhui; He, Haoyu; Luo, Tao; Deng, Huiqiong; Liu, Tieqiao; Hao, Wei; Wang, Jichuan

2015-03-01

Although evidence exists for distinct barriers to drug abuse treatment (BDATs), investigations of their inter-relationships and the effect of individual characteristics on the barrier factors have been sparse, especially in China. A Multiple Indicators Multiple Causes (MIMIC) model is applied for this target. A sample of 262 drug users were recruited from three drug rehabilitation centers in Hunan Province, China. We applied a MIMIC approach to investigate the effect of gender, age, marital status, education, primary substance use, duration of primary drug use, and drug treatment experience on the internal barrier factors: absence of problem (AP), negative social support (NSS), fear of treatment (FT), and privacy concerns (PC). Drug users of various characteristics were found to report different internal barrier factors. Younger participants were more likely to report NSS (-0.19, p=0.038) and PC (-0.31, p<0.001). Compared to other drug users, ice users were more likely to report AP (0.44, p<0.001) and NSS (0.25, p=0.010). Drug treatment experiences related to AP (0.20, p=0.012). In addition, differential item functioning (DIF) occurred in three items when participant from groups with different duration of drug use, ice use, or marital status. Individual characteristics had significant effects on internal barriers to drug treatment. On this basis, BDAT perceived by different individuals could be assessed before tactics were utilized to successfully remove perceived barriers to drug treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

WCPSS Advanced Placement (AP) Test Results, 2009-10. E&R Report No. 10.29

ERIC Educational Resources Information Center

McMillen, Brad

2010-01-01

Analysis of WCPSS' 2009-10 AP reports from the College Board reveal that the number and proportion of WCPSS students taking AP courses and exams continues to grow. Between 1996-97 and 2009-10, the number of students enrolled in WCPSS grew by approximately 63% and the number taking AP exams increased by 238% with a corresponding increase in exams…

Fabrication and characterization of Antheraea pernyi silk fibroin-blended P(LLA-CL) nanofibrous scaffolds for peripheral nerve tissue engineering

NASA Astrophysics Data System (ADS)

Wang, Juan; Sun, Binbin; Bhutto, Muhammad Aqeel; Zhu, Tonghe; Yu, Kui; Bao, Jiayu; Morsi, Yosry; El-Hamshary, Hany; El-Newehy, Mohamed; Mo, Xiumei

2017-03-01

Electrospun nanofibers have gained widespreading interest for tissue engineering application. In the present study, ApF/P(LLA-CL) nanofibrous scaffolds were fabricated via electrospinning. The feasibility of the material as tissue engineering nerve scaffold was investigated in vitro. The average diameter increased with decreasing the blend ratio of ApF to P(LLA-CL). Characterization of 13C NMR and FTIR clarified that there is no obvious chemical bond reaction between ApF and P(LLA-CL). The tensile strength and elongation at break increased with the content increase of P(LLA-CL). The surface hydrophilic property of nanofibrous scaffolds enhanced with the increased content of ApF. Cell viability studies with Schwann cells demonstrated that ApF/P(LLA-CL) blended nanofibrous scaffolds significantly promoted cell growth as compare to P(LLA-CL), especially when the weight ratio of ApF to P(LLA-CL) was 25:75. The present work provides a basis for further studies of this novel nanofibrous material (ApF/P(LLA-CL)) in peripheral nerve tissue repair or regeneration.

Neurotransmitter Release Can Be Stabilized by a Mechanism That Prevents Voltage Changes Near the End of Action Potentials from Affecting Calcium Currents

PubMed Central

Clarke, Stephen G.; Scarnati, Matthew S.

2016-01-01

At chemical synapses, presynaptic action potentials (APs) activate voltage-gated calcium channels, allowing calcium to enter and trigger neurotransmitter release. The duration, peak amplitude, and shape of the AP falling phase alter calcium entry, which can affect neurotransmitter release significantly. In many neurons, APs do not immediately return to the resting potential, but instead exhibit a period of depolarization or hyperpolarization referred to as an afterpotential. We hypothesized that presynaptic afterpotentials should alter neurotransmitter release by affecting the electrical driving force for calcium entry and calcium channel gating. In support of this, presynaptic calcium entry is affected by afterpotentials after standard instant voltage jumps. Here, we used the mouse calyx of Held synapse, which allows simultaneous presynaptic and postsynaptic patch-clamp recording, to show that the postsynaptic response is affected significantly by presynaptic afterpotentials after voltage jumps. We therefore tested the effects of presynaptic afterpotentials using simultaneous presynaptic and postsynaptic recordings and AP waveforms or real APs. Surprisingly, presynaptic afterpotentials after AP stimuli did not alter calcium channel responses or neurotransmitter release appreciably. We show that the AP repolarization time course causes afterpotential-induced changes in calcium driving force and changes in calcium channel gating to effectively cancel each other out. This mechanism, in which electrical driving force is balanced by channel gating, prevents changes in calcium influx from occurring at the end of the AP and therefore acts to stabilize synaptic transmission. In addition, this mechanism can act to stabilize neurotransmitter release when the presynaptic resting potential changes. SIGNIFICANCE STATEMENT The shape of presynaptic action potentials (APs), particularly the falling phase, affects calcium entry and small changes in calcium influx can produce large changes in postsynaptic responses. We hypothesized that afterpotentials, which often follow APs, affect calcium entry and neurotransmitter release. We tested this in calyx of Held nerve terminals, which allow simultaneous recording of presynaptic calcium currents and postsynaptic responses. Surprisingly, presynaptic afterpotentials did not alter calcium current or neurotransmitter release. We show that the AP falling phase causes afterpotential-induced changes in electrical driving force and calcium channel gating to cancel each other out. This mechanism regulates calcium entry at the end of APs and therefore stabilizes synaptic transmission. This also stabilizes responses when the presynaptic resting potential changes. PMID:27911759

Neurotransmitter Release Can Be Stabilized by a Mechanism That Prevents Voltage Changes Near the End of Action Potentials from Affecting Calcium Currents.

PubMed

Clarke, Stephen G; Scarnati, Matthew S; Paradiso, Kenneth G

2016-11-09

At chemical synapses, presynaptic action potentials (APs) activate voltage-gated calcium channels, allowing calcium to enter and trigger neurotransmitter release. The duration, peak amplitude, and shape of the AP falling phase alter calcium entry, which can affect neurotransmitter release significantly. In many neurons, APs do not immediately return to the resting potential, but instead exhibit a period of depolarization or hyperpolarization referred to as an afterpotential. We hypothesized that presynaptic afterpotentials should alter neurotransmitter release by affecting the electrical driving force for calcium entry and calcium channel gating. In support of this, presynaptic calcium entry is affected by afterpotentials after standard instant voltage jumps. Here, we used the mouse calyx of Held synapse, which allows simultaneous presynaptic and postsynaptic patch-clamp recording, to show that the postsynaptic response is affected significantly by presynaptic afterpotentials after voltage jumps. We therefore tested the effects of presynaptic afterpotentials using simultaneous presynaptic and postsynaptic recordings and AP waveforms or real APs. Surprisingly, presynaptic afterpotentials after AP stimuli did not alter calcium channel responses or neurotransmitter release appreciably. We show that the AP repolarization time course causes afterpotential-induced changes in calcium driving force and changes in calcium channel gating to effectively cancel each other out. This mechanism, in which electrical driving force is balanced by channel gating, prevents changes in calcium influx from occurring at the end of the AP and therefore acts to stabilize synaptic transmission. In addition, this mechanism can act to stabilize neurotransmitter release when the presynaptic resting potential changes. The shape of presynaptic action potentials (APs), particularly the falling phase, affects calcium entry and small changes in calcium influx can produce large changes in postsynaptic responses. We hypothesized that afterpotentials, which often follow APs, affect calcium entry and neurotransmitter release. We tested this in calyx of Held nerve terminals, which allow simultaneous recording of presynaptic calcium currents and postsynaptic responses. Surprisingly, presynaptic afterpotentials did not alter calcium current or neurotransmitter release. We show that the AP falling phase causes afterpotential-induced changes in electrical driving force and calcium channel gating to cancel each other out. This mechanism regulates calcium entry at the end of APs and therefore stabilizes synaptic transmission. This also stabilizes responses when the presynaptic resting potential changes. Copyright © 2016 the authors 0270-6474/16/3611559-14$15.00/0.

P1,P4-diadenosine tetraphosphate (Ap4A) inhibits proximal tubular reabsorption of sodium in rats.

PubMed

Stiepanow-Trzeciak, Anna; Jankowski, Maciej; Angielski, Stefan; Szczepanska-Konkel, Miroslawa

2007-01-01

P1,P4-diadenosine tetraphosphate (Ap4A) is a vasoactive dinucleotide possessing natriuretic activity. It is unclear, however, which part of the nephron is the target site of action for Ap4A. We evaluated the tubular sites of Ap4A action using the lithium clearance technique. Ap4A at a priming dose of 2 micromol/kg with subsequent infusion at 20 nmol/kg/min increased fractional water and sodium excretion 2.5- and 5.6-fold, respectively. Moreover, Ap4A increased lithium clearance 1.9-fold and fractional lithium excretion 2.8-fold. Fractional water and sodium excretion from distal nephron segments was not significantly affected by Ap4A. These results suggest that Ap4A induces natriuresis mainly through inhibition of proximal tubular reabsorption of sodium. Copyright 2007 S. Karger AG, Basel.

Encapsulation of ascorbyl palmitate in chitosan nanoparticles by oil-in-water emulsion and ionic gelation processes.

PubMed

Yoksan, Rangrong; Jirawutthiwongchai, Jatesuda; Arpo, Kridsada

2010-03-01

The encapsulation of ascorbyl palmitate (AP) in chitosan particles was carried out by droplet formation via an oil-in-water emulsion, followed by droplet solidification via ionic gelation using sodium triphosphate pentabasic (TPP) as a cross-linking agent. The success of AP encapsulation was confirmed by FT-IR, UV-vis spectrophotometry, TGA, and XRD techniques. The obtained AP-loaded chitosan particles were spherical in shape with an average diameter of 30-100nm as observed by SEM and TEM. Loading capacity (LC) and encapsulation efficiency (EE) of AP in the nanoparticles were about 8-20% and 39-77%, respectively, when the initial AP concentration was in the range of 25-150% (w/w) of chitosan. Augmentation of the initial AP concentration led to an increase of LC and a reduction of EE. The amount of AP released from the nanoparticles in ethanol and tris buffer (pH approximately 8.0) increased with increasing LC and decreasing TPP concentration.

The effects of acetazolamide on arterial pressure variability during REM sleep in the rat.

PubMed

Sone, M; Sei, H; Morita, Y; Ogura, T; Sone, S

1998-01-01

During rapid eye movement (REM) sleep, the arterial pressure (AP) undergoes large fluctuations in the rat, cat, and other mammals, including humans, and it has been suggested that this effect originates in the forebrain. In addition, acetazolamide (ACTZ), a carbonic anhydrase inhibitor, is known to be effective in the treatment of central sleep apnea or epilepsy. The aim of the present study was to analyze the effects of ACTZ on EEG theta rhythm and AP variability during REM sleep in rats. Treatment consisted of intraperitoneal injection of 5 mg of ACTZ in 0.5 mL of saline (n = 6) or 0.5 mL of vehicle alone (n = 6). We then recorded and analyzed the mean AP (MAP) variations during different sleep phases, using a telemetric system. Our results show: 1) Significant decreases in the coefficient of variation of MAP, in the very-low frequency (0.025 - 0.225 Hz) component of the power spectral density of the AP and in theta frequency in the electroencephalogram, were seen in the ACTZ-treated group during REM sleep compared with controls, whereas no significant difference was found between the two groups in non-REM sleep. There was no significant difference in sleep duration, average MAP, and heart rate between the groups. Our data suggest that ACTZ may act as a stabilizing factor preventing AP fluctuations during REM sleep.

OXIDATIVE STRESS AND TREG DEPLETION IN LUPUS PATIENTS WITH ANTI-PHOSPHOLIPID SYNDROME

PubMed Central

Lai, Zhi-wei; Marchena-Mendez, Ivan; Perl, Andras

2015-01-01

Anti-phospholipid antibodies (APLA) represent a diagnostic criterion of systemic lupus erythematosus (SLE) and cause morbidity, termed anti-phospholipid syndrome (APS). Activation of the mechanistic target of rapamycin (mTOR) has been recently associated with APS. mTOR is a sensor of oxidative stress. Therefore, we examined mitochondrial mass, superoxide production, mTOR and FoxP3 expression in 72 SLE patients, twelve of whom also had APS, and 54 healthy controls by flow cytometry. Mitochondrial mass was increased in CD4−CD8− double-negative (DN) T cells of SLE patients with APS (2.7-fold) in comparison to those without APS (1.7-fold; p=0.014). Superoxide production was increased in all lymphocyte subsets of APS patients. FoxP3+ cells were depleted within CD4+CD25+ Tregs in patients with APS (28.4%) relative to those without APS (46.3%, p=0.008). mTOR activity was similar between SLE patients with and without APS. Thus, oxidative stress and Treg depletion rather than mTOR activation underlie APS in patients with SLE. PMID:25862984

Quantifying performance and effects of load carriage during a challenging balancing task using an array of wireless inertial sensors.

PubMed

Cain, Stephen M; McGinnis, Ryan S; Davidson, Steven P; Vitali, Rachel V; Perkins, Noel C; McLean, Scott G

2016-01-01

We utilize an array of wireless inertial measurement units (IMUs) to measure the movements of subjects (n=30) traversing an outdoor balance beam (zigzag and sloping) as quickly as possible both with and without load (20.5kg). Our objectives are: (1) to use IMU array data to calculate metrics that quantify performance (speed and stability) and (2) to investigate the effects of load on performance. We hypothesize that added load significantly decreases subject speed yet results in increased stability of subject movements. We propose and evaluate five performance metrics: (1) time to cross beam (less time=more speed), (2) percentage of total time spent in double support (more double support time=more stable), (3) stride duration (longer stride duration=more stable), (4) ratio of sacrum M-L to A-P acceleration (lower ratio=less lateral balance corrections=more stable), and (5) M-L torso range of motion (smaller range of motion=less balance corrections=more stable). We find that the total time to cross the beam increases with load (t=4.85, p<0.001). Stability metrics also change significantly with load, all indicating increased stability. In particular, double support time increases (t=6.04, p<0.001), stride duration increases (t=3.436, p=0.002), the ratio of sacrum acceleration RMS decreases (t=-5.56, p<0.001), and the M-L torso lean range of motion decreases (t=-2.82, p=0.009). Overall, the IMU array successfully measures subject movement and gait parameters that reveal the trade-off between speed and stability in this highly dynamic balance task. Copyright © 2015 Elsevier B.V. All rights reserved.

Comparison of Outcomes in 3 Surgical Approaches for Dystrophic Cervical Kyphosis in Patients with Neurofibromatosis 1.

PubMed

Lin, Tao; Shao, Wei; Zhang, Ke; Gao, Rui; Zhou, Xuhui

2018-03-01

To compare outcomes of anterior-only (AO), posterior-only (PO), and anteroposterior (AP) surgical approaches for treatment of dystrophic cervical kyphosis in patients with neurofibromatosis 1 (NF1). This retrospective observational study included 81 patients with dystrophic cervical kyphosis secondary to NF1. Length of kyphosis, duration of halo traction, Cobb angle, C2-7-sagittal vertical axis (SVA), T1 slope, Neck Disability Index score, and postoperative complications were evaluated before and, if possible, after each surgical approach. AP approach provided the best outcomes (average spinal Cobb angle was corrected from 61.2 ± 9.1° to 5.7 ± 3.2°, P < 0.05); there was no significant difference between AO and PO approaches (P > 0.05). With regard to cervical sagittal balance, AP approach had the most improvements of C2-7-SVA (mean C2-7-SVA was corrected from 3.2 ± 9.2 mm to 12.8 ± 2.6 mm, P < 0.05); the difference between AO and PO approaches was not significant (P > 0.05). T1 slope results were similar to C2-7-SVA. Neck Disability Index score of all patients improved significantly after surgery (P < 0.05); specifically, patients who had an AP approach constituted the largest portion of the satisfied patient group. Postoperative junctional kyphosis occurred in 11 patients (1 AP approach, 6 AO approach, 4 PO approach); these findings correlated with patients with ≤5 fused segments. AP approach surgery provided the best correction of dystrophic cervical kyphosis and sagittal balance for patients with NF1. Patients undergoing an AP approach were more satisfied with their outcomes. Junctional kyphosis can be prevented effectively using an AP approach in patients with >5 fused segments. Copyright © 2017 Elsevier Inc. All rights reserved.

Reassessment of area postrema's role in motion sickness and conditioned taste aversion

NASA Technical Reports Server (NTRS)

Daunton, Nancy G.; Brizzee, Kenneth R.; Corcoran, Meryl Lee; Crampton, G. H.; Damelio, F.; Elfar, S.; Fox, Robert A.

1991-01-01

On the basis of classical studies on the role of the area psotrema (AP) in motion-induced emesis it was generally accepted that the AP is an essential structure for the production of vomiting in response to motion. However, in more recent studies it has been demonstrated that vomiting induced by motion can still occur in animals in which the AP has been destroyed bilaterally. It was inferred from some of these more recent studies that the AP plays no role in motion-induced emesis. From the standpoint of the current understanding of central nervous system (CNS) plasticity, redundancy, remodeling, unmasking, regeneration, and recovery of function, however, it is important to realize the limitations of using ablation procedures to determine the functional role of a given neural structure in a highly integrated, adaptable central nervous system (CNS). For example, the results of our recent investigations in cat and squirrel monkey on the role of the AP in emesis and conditioned taste aversion induced by motion indicate that while AP lesions do not prevent motion-induced emesis when animals are tested 30 days or more after surgery, the lesions do change the latency to emesis. Thus, contradictory findings from lesion studies must be evaluated not only in terms of species difference, differences in lesioning techniques and extent of lesions, and in stimulus parameters, but also in terms of duration of the recovery period, during which significant recovery of function may take place. In our judgment, inadequate consideration of the foregoing factors could lead to erroneous inferences about given structure's role in the behavior of the intact, nonablated animal.

The Time Is Up: Compression of Visual Time Interval Estimations of Bimodal Aperiodic Patterns

PubMed Central

Duarte, Fabiola; Lemus, Luis

2017-01-01

The ability to estimate time intervals subserves many of our behaviors and perceptual experiences. However, it is not clear how aperiodic (AP) stimuli affect our perception of time intervals across sensory modalities. To address this question, we evaluated the human capacity to discriminate between two acoustic (A), visual (V) or audiovisual (AV) time intervals of trains of scattered pulses. We first measured the periodicity of those stimuli and then sought for correlations with the accuracy and reaction times (RTs) of the subjects. We found that, for all time intervals tested in our experiment, the visual system consistently perceived AP stimuli as being shorter than the periodic (P) ones. In contrast, such a compression phenomenon was not apparent during auditory trials. Our conclusions are: first, the subjects exposed to P stimuli are more likely to measure their durations accurately. Second, perceptual time compression occurs for AP visual stimuli. Lastly, AV discriminations are determined by A dominance rather than by AV enhancement. PMID:28848406

Extraterrestrial Hemorrhage Control: Terrestrial Developments in Technique, Technology, and Philosophy with Applicability to Traumatic Hemorrhage Control in Long-Duration Spaceflight

DTIC Science & Technology

2005-01-01

instability, or allow oxygen- ation of a patient suffering from a severe respiratory insult such as a massive toxic inhalation , but would be unsatisfactory... trehalose survive freeze-drying. Cryobiology 2001; 42:79–87. 151. Fischer TH, Merricks EP, Bode AP, et al. Thrombus formation with rehydrated

Dampened neural activity and abolition of epileptic-like activity in cortical slices by active ingredients of spices

PubMed Central

Pezzoli, Maurizio; Elhamdani, Abdeladim; Camacho, Susana; Meystre, Julie; González, Stephanie Michlig; le Coutre, Johannes; Markram, Henry

2014-01-01

Active ingredients of spices (AIS) modulate neural response in the peripheral nervous system, mainly through interaction with TRP channel/receptors. The present study explores how different AIS modulate neural response in layer 5 pyramidal neurons of S1 neocortex. The AIS tested are agonists of TRPV1/3, TRPM8 or TRPA1. Our results demonstrate that capsaicin, eugenol, menthol, icilin and cinnamaldehyde, but not AITC dampen the generation of APs in a voltage- and time-dependent manner. This effect was further tested for the TRPM8 ligands in the presence of a TRPM8 blocker (BCTC) and on TRPM8 KO mice. The observable effect was still present. Finally, the influence of the selected AIS was tested on in vitro gabazine-induced seizures. Results coincide with the above observations: except for cinnamaldehyde, the same AIS were able to reduce the number, duration of the AP bursts and increase the concentration of gabazine needed to elicit them. In conclusion, our data suggests that some of these AIS can modulate glutamatergic neurons in the brain through a TRP-independent pathway, regardless of whether the neurons are stimulated intracellularly or by hyperactive microcircuitry. PMID:25359561

Coronary effects of diadenosine tetraphosphate resemble those of adenosine in anesthetized pigs: involvement of ATP-sensitive potassium channels.

PubMed

Nakae, I; Takahashi, M; Takaoka, A; Liu, Q; Matsumoto, T; Amano, M; Sekine, A; Nakajima, H; Kinoshita, M

1996-07-01

Diadenosine tetraphosphate (Ap4A) is an adenine nucleotide with vasodilatory properties. We examined the effects of Ap4A on coronary circulation in comparison with those of adenosine, its metabolite, in anesthetized pigs. Left atrial (LA) infusion of Ap4A at increasing doses of 100, 200, and 300 micrograms/kg/min increased coronary blood flow (CBF) and decreased systemic blood pressure (BP) and coronary vascular resistance (CVR). Ap4A had no effect on large epicardial coronary artery diameter (CoD). Likewise, LA infusion of adenosine at doses of 150 and 300 micrograms/kg/min increased CBF and decreased BP and coronary vascular resistance (CVR) but did not affect CoD. Therefore, the vasodilatory effects of Ap4A and adenosine were predominant in small coronary resistance vessels and negligible in large coronary arteries. Pretreatment with glibenclamide (2 mg/kg, intravenously, i.v.), a specific blocker of ATP-sensitive potassium channels (KATP), attenuated alterations of CBF, BP, and CVR induced by Ap4A and by adenosine. In contrast, treatment with cromakalim (0.5 microgram/kg/min i.v.), an activator of KATP, enhanced the coronary effects of Ap4A and adenosine. Therefore, the opening of KATP in the pig coronary circulation is involved in the in vivo vasodilatory effects of Ap4A and adenosine. Treatment with 8-phenyltheophylline (8-PT, 4 mg/kg i.v.), an adenosine receptor antagonist, suppressed CBF increases induced by Ap4A (20 micrograms/kg/min, intracoronarily, i.c.) and adenosine (5 micrograms/kg/min i.c.) by 68 and 90%, respectively. These findings suggest that the in vivo coronary effects of Ap4A are largely caused by the opening of KATP through rapid degradation to adenosine to activate adenosine receptors.

Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate.

PubMed

Peters, E; Geraci, S; Heemskerk, S; Wilmer, M J; Bilos, A; Kraenzlin, B; Gretz, N; Pickkers, P; Masereeuw, R

2015-10-01

Recently, two phase-II trials demonstrated improved renal function in critically ill patients with sepsis-associated acute kidney injury treated with the enzyme alkaline phosphatase. Here, we elucidated the dual active effect on renal protection of alkaline phosphatase. The effect of human recombinant alkaline phosphatase (recAP) on LPS-induced renal injury was studied in Sprague-Dawley rats. Renal function was assessed by transcutaneous measurement of FITC-sinistrin elimination in freely moving, awake rats. The mechanism of action of recAP was further investigated in vitro using conditionally immortalized human proximal tubular epithelial cells (ciPTEC). In vivo, LPS administration significantly prolonged FITC-sinistrin half-life and increased fractional urea excretion, which was prevented by recAP co-administration. Moreover, recAP prevented LPS-induced increase in proximal tubule injury marker, kidney injury molecule-1 expression and excretion. In vitro, LPS-induced production of TNF-α, IL-6 and IL-8 was significantly attenuated by recAP. This effect was linked to dephosphorylation, as enzymatically inactive recAP had no effect on LPS-induced cytokine production. RecAP-mediated protection resulted in increased adenosine levels through dephosphorylation of LPS-induced extracellular ADP and ATP. Also, recAP attenuated LPS-induced increased expression of adenosine A2A receptor. However, the A2A receptor antagonist ZM-241385 did not diminish the effects of recAP. These results indicate that the ability of recAP to reduce renal inflammation may account for the beneficial effect observed in septic acute kidney injury patients, and that dephosphorylation of ATP and LPS are responsible for this protective effect. © 2015 The British Pharmacological Society.

[Effect of Moxibustion on Learning-memory Ability and Hippocampal Amyloid beta Protein Overexpression in Mild Cognitive Impairment Rats].

PubMed

Zhu, Cai-feng; Sun, Jian-jian; Han, Wei; Yang, Jun

2016-04-01

To observe the effect of moxibustion of "Baihui" (GV 20), etc. on learning-memory ability, hip- pocampal amyloid beta (AP) protein expression and immune activity in mild cognitive impairment (MCI) rats, so as to reveal its mechanism underlying improving cognitive impairment. A total of 48 SD rats were randomly divided into normal, model, moxibustion, and medication groups (n = 12 in each group). The MCI model was established by intraperitoneal injection of 2 mL mixture solution containing D-galactose (120 mg - kg- - d-) and Sodium Nitrite (90 mg x kg(-1) x d(-1)), once daily for 40 days. Moxibustion (separated by Radix Aconiti Praeparata cake) was applied to "Baihui" (GV 20), "Fengfu" (GV 16) and "Dazhui" (GV 14) for 20 min, once daily for 2 weeks, with one day's rest between two weeks. The rats of the medication group were given with Nimodipine (2 mg x kg(-1) x d(-1), t.i.d.) by lavage for 2 weeks (except Sundays). The learning-memory ability was detected by Morris maze water swimming tasks. The expression level of hippocampal AP protein was detected by immunohistochemistry, and those of hippocampal presenilin-1 (PS-1) mRNA and cleaving enzyme (BACE-1) mRNA were detected by real time-PCR, and serum IL-6 level was assayed by ELISA. Following modeling, the average escape latency of location navigation tests of Morris maze water swimming tests, the expression levels of hippocampal Abeta protein, PS-1 mRNA and BACE-1 mRNA, and serum IL-6 content were significantly increased in the model group( P<0.01) , while the target-platform crossing times and the percentage of target-quadrant swimming duration of spacial probe trials were remarkably decreased in the model group (P<0.01). After moxibustion, the increased escape latency, hippocampal AP protein, PS-i mHNA and BACE-1 mRNA ex- pression and serum IL-6 content, and the decreased target-platform crossing times and the percentage of target-quadrant swim- ming duration were reversed in both moxibustion and medication groups (P<0.01). The effects of the moxibustion group were obviously superior to those of the medication group in decreasing the escape latency, and in up-regulating the target-platform crossing times, the percentage of target-quadrant swimming duration, and down-regulating hippocampal Abeta protein, PS-1 mHNA and BACE-1 mRNA expression levels and serum IL-6 content (P<0.05). Moxibustion is effective in improving MCI rats' learning-memory ability, which may be associated with its functions in down-regulating the levels of hippocampal Abeta protein, PS-1 mRNA and BACE-1 mRNA expression and serum IL-6 content, possibly by blocking Abeta overexpression-induced inflammation cascade.

Perspectives of Advanced Placement U.S. History Teachers in Title I Schools

ERIC Educational Resources Information Center

Rowland, Mark Lance

2017-01-01

The College Board's Advanced Placement (AP) Program continues to expand annually with increased numbers of high school students nationwide enrolling in AP courses and taking end-of-course AP exams, in hopes of earning college credit and strengthening high school transcripts. As the College Board promotes increased minority student participation…

Inositol-1,4,5-trisphosphate increase by diadenosine tetraphosphate in preparations from failing human myocardium.

PubMed

Knapp, J; Bokník, P; Linck, B; Läer, S; Müller, F U; Neumann, J; Vahlensieck, U; Schlüter, H; Zidek, W; Schmitz, W

1999-09-01

In human ventricular trabeculae carneae 100 microM AP4A (diadenosine tetraphosphate) increased force of contraction to 162.8+/-15.7% of predrug value (n=9). This positive inotropic effect was accompanied by a prolongation of time parameters: time to peak tension and time of relaxation were prolonged by 7.8+/-1.3% and 14.9+/-3.8%, respectively (P<0.05). In the same trabeculae, AP4A increased IP3 (inositol-1,4,5-trisphosphate) content from 9.0+/-1.3 pmol/mg to 22.9+/-5.4 pmol/mg protein (n=5-9). In conclusion, the positive inotropic effect of AP4A in the human myocardium is likely due to an increase of IP3 mediated probably via Gq-coupled P2Y-purinoceptors. Because of the prominent role of Gq in the development of cardiac disease, these findings may lay the ground to further investigate the possible role of AP4A and/or related ligands (e.g. AP2A and AP3A) in heart failure.

Transit Timing Variation analysis with Kepler light curves of KOI 227 and Kepler 93b

NASA Astrophysics Data System (ADS)

Dulz, Shannon; Reed, Mike

2017-01-01

By searching for transit signals in approximately 150,000 stars, NASA’s Kepler Space telescope found thousands of exoplanets over its primary mission from 2009 to 2013 (Tenenbaum et al. 2014, ApJS, 211, 6). Yet, a detailed follow-up examination of Kepler light curves may contribute more evidence on system dynamics and planetary atmospheres of these objects. Kepler’s continuous observing of these systems over the mission duration produced light curves of sufficient duration to allow for the search for transit timing variations. Transit timing variations over the course of many orbits may indicate a precessing orbit or the existence of a non-transiting third body such as another exoplanet. Flux contributions of the planet just prior to secondary eclipse may provide a measurement of bond albedo from the day-side of the transiting planet. Any asymmetries of the transit shape may indicate thermal asymmetries which can measure upper atmosphere motion of the planet. These two factors can constrain atmospheric models of close orbiting exoplanets. We first establish our procedure with the well-documented TTV system, KOI 227 (Nesvorny et al. 2014, ApJ, 790, 31). Using the test case of KOI 227, we analyze Kepler-93b for TTVs and day-side flux contributions. Kepler-93b is likely a rocky planet with R = 1.50 ± 0.03 Earth Radii and M = 2.59 ± 2.0 Earth Masses (Marcy et al. 2014, ApJS, 210, 20). This research is funded by a NASA EPSCoR grant.

Air and Water Processes Do Not Produce the Same High-Quality Pasteurization of Donor Human Milk.

PubMed

Buffin, Rachel; Pradat, Pierre; Trompette, Jocelyne; Ndiaye, Isabelle; Basson, Eliane; Jordan, Isabelle; Picaud, Jean-Charles

2017-11-01

Holder pasteurization is the most commonly used technique in milk banks worldwide, but higher temperatures and longer pasteurization time have been associated with damage to the immune components of human milk. Research aim: This study aimed to assess the detailed pattern of pasteurization temperature using two water pasteurizers (WP1 and WP2) and one air pasteurizer (AP). The milk temperature during each phase of the pasteurization cycle was recorded using 6 to 9 probes, depending on the number of bottles, in the pasteurizers. We used 90 to 200 ml bottles to assess the effect of volume on milk temperature. The time to heat the milk from room temperature to 58°C was 12.4, 12.9, and 64.5 min, respectively, for WP1, WP2, and the AP ( p < .0001). The duration of the plateau was 35.5, 35.2, and 45.8 min ( p < .0001). The duration of exposure to a temperature above 58°C was 49.6, 40.7, and 76.2 min ( p < .0001). The total duration of a full cycle was 79, 66, and 182 min ( p < .0001). The duration of exposure above 58°C for the different volumes of milk treated showed no difference when using WP1 but was significantly longer in small volumes when using WP2. Human milk treated using the air pasteurizer in our study was exposed to higher temperatures and for longer periods of time than the water pasteurizers we employed. Regular qualification of pasteurizers is requested when evaluating the effect of pasteurization on milk components and for routine treatment of human milk in milk banks.

Effects of organic acids and essential oils blend on growth, gut microbiota, immune response and disease resistance of Pacific white shrimp (Litopenaeus vannamei) against Vibrio parahaemolyticus.

PubMed

He, Wangquan; Rahimnejad, Samad; Wang, Ling; Song, Kai; Lu, Kangle; Zhang, Chunxiao

2017-11-01

An 8-week feeding trial was undertaken to evaluate supplemental effects of AviPlus ® (AP), a blend of organic acids [citric acid, 25%; sorbic acid, 16.7%] and essential oils [thymol, 1.7%; vanillin, 1.0%], on growth, gut microbiota, innate immunity and disease resistance of Pacific white shrimp (Litopenaeus vannamei) against Vibrio parahaemolyticus. A basal experimental diet was formulated and supplemented with 0, 0.3, 0.6, 0.9 and 1.2 g kg -1  AP to produce five test diets (Con, AP0.3, AP0.6, AP0.9 and AP1.2). Each diet was fed to triplicate groups of shrimp (0.2 ± 0.01 g, mean ± SE) to apparent satiation three times daily. Growth performance and survival rate were not significantly influenced by AP supplementation (P > 0.05). Significantly (P < 0.05) higher serum total protein was found in groups fed ≥ 0.6 g kg -1  AP compared to control. Serum alkaline phosphatase and phenoloxidase activities were significantly increased in AP0.9 and AP1.2 groups. Also, the group received AP0.6 diet showed significantly higher glutathione peroxidase activity than control. Expression of gut pro-inflammatory genes including TNF-α, LITAF and RAB6A were down-regulated by AP administration. Gut microbiota analysis showed the significant enhancement of the operational taxonomic unit (OTU) diversity and richness indices by AP application. AP supplementation led to increased abundance of Firmicutes and a reduction in abundance of Proteobacteria. Also, dietary inclusion of 1.2 g kg -1  AP led to a significant increase in the abundance of Lactobacillus in shrimp gut. The group offered AP0.3 diet showed significantly higher disease resistance than control group. Furthermore, AP application significantly enhanced relative expression of immune related genes including lysozyme, penaeidin and catalase at 48 h post challenge. In conclusion, these findings show that the tested organic acids and essential oils mixture beneficially affects intestinal microflora and improves immune response and disease resistance of L. vannamei. Copyright © 2017 Elsevier Ltd. All rights reserved.

Independent Epileptiform Discharge Patterns in the Olfactory and Limbic Areas of the In Vitro Isolated Guinea Pig Brain During 4-Aminopyridine Treatment

PubMed Central

Carriero, Giovanni; Uva, Laura; Gnatkovsky, Vadym; Avoli, Massimo; de Curtis, Marco

2016-01-01

In vitro studies performed on brain slices demonstrate that the potassium channel blocker 4-aminopyridine (4AP, 50 μM) discloses electrographic seizure activity and interictal discharges. These epileptiform patterns have been further analyzed here in a isolated whole guinea pig brain in vitro by using field potential recordings in olfactory and limbic structures. In 8 of 13 experiments runs of fast oscillatory activity (fast runs, FRs) in the piriform cortex (PC) propagated to the lateral entorhinal cortex (EC), hippocampus and occasionally to the medial EC. Early and late FRs were asynchronous in the hemispheres showed different duration [1.78 ± 0.51 and 27.95 ± 4.55 (SD) s, respectively], frequency of occurrence (1.82 ± 0.49 and 34.16 ± 6.03 s) and frequency content (20–40 vs. 40–60 Hz). Preictal spikes independent from the FRs appeared in the hippocampus/EC and developed into ictal-like discharges that did not propagate to the PC. Ictal-like activity consisted of fast activity with onset either in the hippocampus (n = 6) or in the mEC (n = 2), followed by irregular spiking and sequences of diffusely synchronous bursts. Perfusion of the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid (100 μM) did not prevent FRs, increased the duration of limbic ictal-like discharges and favored their propagation to olfactory structures. The AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (50 μM) blocked ictal-like events and reduced FRs. In conclusion, 4AP-induced epileptiform activities are asynchronous and independent in olfactory and hippocampal-entorhinal regions. Epileptiform discharges in the isolated guinea pig brain show different pharmacological properties compared with rodent in vitro slices. PMID:20220076

Cell Death and DAMPs in Acute Pancreatitis

PubMed Central

Kang, Rui; Lotze, Michael T; Zeh, Herbert J; Billiar, Timothy R; Tang, Daolin

2014-01-01

Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP. Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP. DAMPs might be an attractive therapeutic target in AP. PMID:25105302

Glutamyl aminopeptidase in microvesicular and exosomal fractions of urine is related with renal dysfunction in cisplatin-treated rats.

PubMed

Quesada, Andrés; Segarra, Ana Belén; Montoro-Molina, Sebastián; de Gracia, María Del Carmen; Osuna, Antonio; O'Valle, Francisco; Gómez-Guzmán, Manuel; Vargas, Félix; Wangensteen, Rosemary

2017-01-01

The aim of this work was to investigate if the content of glutamyl aminopeptidase (GluAp) in microvesicular and exosomal fractions of urine is related with renal dysfunction in cisplatin-treated rats. Urine samples were collected 24 hours after injection of cisplatin (7 mg/kg, n = 10) or saline serum (n = 10), and they were subjected to differential centrifugation at 1.000, 17.000 and 200.000 g to obtain microvesicular and exosomal fractions. GluAp was measured with a commercial ELISA kit in both fractions. Serum creatinine (SCr) and body weight were measured 15 days after treatment. We analyzed if early excretion of GluAp in microsomal and exosomal fractions was correlated with final SCr and body weight increase. In a second experiment, enzymatic activities of GluAp and alanyl aminopeptidase (AlaAp) in urine, microvesicular and exosomal fractions were measured three days after injection. We analyzed the correlation of both markers with SCr determined at this point. Finally, we studied the expression of GluAp and extracellular vesicles markers Alix and tumor susceptibility gene (TSG101) in both fractions by immunoblotting. GluAp excretion was increased in all fractions of urine after cisplatin treatment, even if data were normalized per mg of creatinine, per body weight or per total protein content of each fraction. We found significant predictive correlations with SCr concentration, and inverse correlations with body weight increase determined 15 days later. Three days after injection, aminopeptidasic activities were markedly increased in all fractions of urine in cisplatin-treated rats. The highest correlation coefficient with SCr was found for GluAp in microvesicular fraction. Increase of GluAp in microvesicular and exosomal fractions from cisplatin-treated rats was confirmed by immunoblotting. Alix and TSG101 showed different patterns of expression in each fraction. Determination of GluAp content or its enzymatic activity in microvesicular and exosomal fractions of urine is an early and predictive biomarker of renal dysfunction in cisplatin-induced nephrotoxicity. Measurement of GluAp in these fractions can serve to detect proximal tubular damage independently of glomerular filtration status.

Sugary Kefir Strain Lactobacillus mali APS1 Ameliorated Hepatic Steatosis by Regulation of SIRT-1/Nrf-2 and Gut Microbiota in Rats.

PubMed

Chen, Yung-Tsung; Lin, Yu-Chun; Lin, Jin-Seng; Yang, Ning-Sun; Chen, Ming-Ju

2018-04-01

Non-alcoholic fatty liver disease (NAFLD) is a common disease that is concomitant with obesity, resulting in increased mortality. To date, the efficiency of NAFLD treatment still needs to be improved. Therefore, we aimed to evaluate the effect of Lactobacillus mali APS1, which was isolated from sugary kefir, on hepatic steatosis in rats fed a high-fat diet (HFD). Sprague Dawley rats were fed a control diet, a HFD with saline, and a HFD with APS1 intervention by gavage daily for 12 weeks. The results showed that APS1 significantly reduced body weight and body weight gain in HFD-fed rats. APS1 reduced hepatic lipid accumulation by regulating SIRT-1/PGC-1α/SREBP-1 expression. Moreover, APS1 increased hepatic antioxidant activity by modulating Nrf-2/HO-1 expression. Notably, APS1 manipulated the gut microbiota, resulting in increasing proportions of the phylum Bacteroidetes/Firmicutes and reducing the abundance of specific NAFLD-associated bacteria. These results suggested that APS1 ameliorated hepatic steatosis by modulating lipid metabolism and antioxidant activity via manipulating specific NAFLD-associated gut microbiota in vivo. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Changes in diadenosine tetraphosphate levels in Physarum polycephalum with different oxygen concentrations.

PubMed Central

Garrison, P N; Mathis, S A; Barnes, L D

1989-01-01

Cellular levels of diadenosine tetraphosphate (Ap4A) were measured, by a specific high-pressure liquid chromatography method, in microplasmodia of Physarum polycephalum subjected to different degrees of hypoxia, hyperoxia, and treatment with H2O2. Ap4A levels increased three- to sevenfold under anaerobic conditions, and the microplasmodia remained viable after such treatment. Elevated levels of Ap4A returned to the basal level within 5 to 10 min upon reoxygenation of the microplasmodia. The increases in Ap4A levels were larger in stationary-phase or starved microplasmodia than in fed, log-phase microplasmodia. The maximal increase measured in log-phase microplasmodia was twofold. No significant changes in Ap4A levels occurred in microplasmodia subjected to mild hypoxia, hyperoxia, or treatment with 1 mM H2O2. These results indicate that in P. polycephalum, Ap4A may function in the metabolic response to anaerobic conditions rather than in the response to oxidative stress. PMID:2921243

Molecular dynamics simulations of AP/HMX composite with a modified force field.

PubMed

Zhu, Wei; Wang, Xijun; Xiao, Jijun; Zhu, Weihua; Sun, Huai; Xiao, Heming

2009-08-15

An all-atom force field for ammonium perchlorate (AP) is developed with the framework of pcff force field. The structural parameters of AP obtained with the modified force field are in good agreement with experimental values. Molecular dynamics (MD) simulations have been performed to investigate AP/HMX (1,3,5,7-tetranitro-1,3,5,7-tetrazocane) composite at different temperatures. The binding energies, thermal expansion coefficient, and the trigger bond lengths of HMX in the AP/HMX composite have been obtained. The binding energies of the system increase slightly with temperature increasing, peak at 245K, and then gradually decrease. The volume thermal expansion coefficient of the AP/HMX composite has been derived from the volume variation with temperature. As the temperature rises, the maximal lengths of the trigger bond N-NO(2) of HMX increase gradually. The simulated results indicate that the maximal length of trigger bond can be used as a criterion for judging the sensitivity of energetic composite.

VizieR Online Data Catalog: Cosmic evolution of long gamma-ray burst luminosity (Deng+, 2016)

NASA Astrophysics Data System (ADS)

Deng, C.-M.; Wang, X.-G.; Guo, B.-B.; Lu, R.-J.; Wang, Y.-Z.; Wei, J.-J.; Wu, X.-F.; Liang, E.-W.

2018-02-01

Our sample includes only the redshift-known long GRBs observed with Swift/BAT from 2005 January to 2015 April. Low-luminosity GRBs are excluded since they may belong to another distinct population (e.g., Chapman et al. 2007MNRAS.382L..21C; Liang et al. 2007ApJ...662.1111L; Lu et al. 2010ApJ...725.1965L). Although the durations of some GRBs, such as GRB 050724 and GRB 060614, are larger than 2s, we do not include them in our sample since they may be from merger of compact stars (Berger et al. 2005Natur.438..988B; Gehrels et al. 2006Natur.444.1044G; Zhang et al. 2007ApJ...655L..25Z, 2009ApJ...703.1696Z). The afterglow and host galaxy observations of the high-z SGRB GRB 090426 (T90=1.2s) show that it may be from the collapse of a massive star (Antonelli et al. 2009A&A...507L..45A; Xin et al. 2011MNRAS.410...27X). We thus include this GRB in our sample. We finally obtain a sample of 258 GRBs. They are reported in Table 1. (1 data file).

Development of a dialyzer with enhanced internal filtration to increase the clearance of low molecular weight proteins.

PubMed

Fujimura, Takayasu; Uchi, Yukihiko; Fukuda, Makoto; Miyazaki, Miwa; Uezumi, Satoshi; Hiyoshi, Tatsuo

2004-01-01

Accumulated low molecular weight proteins in hemodialysis patients require a high-flux dialyzer. There have been several methods proposed for enhancing internal filtration, including narrowing the inside diameter of the hollow fibers, lengthening the fibers, and increasing the fiber density ratio. We tried to enhance the internal filtration by increasing the pressure drop in the dialysate compartment through increasing the fiber density ratio. If the fiber density ratio is too high, however, an irregular dialysate path may result, thus decreasing dialysis performance. Therefore, we took note of the shape of the inner housing and added a short taper structure, which improved the dialysate path dramatically. Consequently, we developed an internal filtration-enhanced dialyzer (APS-Prototype) to improve dialysis performance. The internal filtration rate in water (measured by Doppler ultrasound) was 13.2 l/session for the APS-Prototype and 5.3 l/session for the APS-15E. The amount of alpha1-microglobulin (alpha1-MG) in bovine plasma was 0.34 g for the APS-Prototype and 0.11 g for the APS-15E. In addition, the amount of alpha1-MG in vivo was 29.0% +/- 5.8% for the APS-Prototype, significantly higher than that for the APS-15E (13.6% +/- 1.9%). The desirable loss of albumin is 2-4 g in hemodiafiltration, and it was 3.92 +/- 1.03 g for the APS-Prototype. The prototype showed excellent solute removal performance with no clinical or engineering problems.

Characteristic Times of Gradual Solar Energetic Particle Events and Their Dependence on Associated Coronal Mass Ejection Properties

DTIC Science & Technology

2005-08-01

Campbell 1996). differences, including longer event durations for SEPs from quasi- Yago & Kamide (2003) have shown that the lognormal plot is...Howard, R. A. 2003, Urpo, S. 1999, A&A, 348, 271 ApJ, 598, 1392 Klein, K.-L., & Trottet, G. 2001, Space Sci. Rev., 95, 215 Yago , K., & Kamide, Y. 2003

Influence of apple pomace inclusion on the process of animal feed pelleting.

PubMed

Maslovarić, Marijana D; Vukmirović, Đuro; Pezo, Lato; Čolović, Radmilo; Jovanović, Rade; Spasevski, Nedeljka; Tolimir, Nataša

2017-08-01

Apple pomace (AP) is the main by-product of apple juice production. Large amounts of this material disposed into landfills can cause serious environmental problems. One of the solutions is to utilise AP as animal feed. The aim of this study was to investigate the impact of dried AP inclusion into model mixtures made from conventional feedstuffs on pellet quality and pellet press performance. Three model mixtures, with different ratios of maize, sunflower meal and AP, were pelleted. Response surface methodology (RSM) was applied when designing the experiment. The simultaneous and interactive effects of apple pomace share (APS) in the mixtures, die thickness (DT) of the pellet press and initial moisture content of the mixtures (M), on pellet quality and production parameters were investigated. Principal component analysis (PCA) and standard score (SS) analysis were applied for comprehensive analysis of the experimental data. The increase in APS led to an improvement of pellet quality parameters: pellet durability index (PDI), hardness (H) and proportion of fines in pellets. The increase in DT and M resulted in pellet quality improvement. The increase in DT and APS resulted in higher energy consumption of the pellet press. APS was the most influential variable for PDI and H calculation, while APS and DT were the most influential variables in the calculation of pellet press energy consumption. PCA showed that the first two principal components could be considered sufficient for data representation. In conclusion, addition of dried AP to feed model mixtures significantly improved the quality of the pellets.

The absorption and transport of magnolol in Caco-2 cell model.

PubMed

Wu, An-Guo; Zeng, Bao; Huang, Meng-Qiu; Li, Sheng-Mei; Chen, Jian-Nan; Lai, Xiao-Ping

2013-03-01

To investigate the absorption and transport mechanism of magnolol in Caco-2 cell model. A human intestinal epithelial cell model Caco-2 cell in vitro cultured was applied to study the absorption and transport of magnolol, the effects of time, donor concentration, P-gp inhibitor verapamil, pH and temperature on the absorption and transport of magnolol were investigated. The determination of magnolol was performed by high performance liquid chromatography, then the values of apparent permeability coefficient (P app ) and P ratio Basolateral-to-Apical (BL-to-AP)/Apical-to-Basolateral (AP-to-BL) were calculated. In Caco-2 cell model, comparing the amounts of transport of AP-to-BL and BL-to-AP, the latter was larger. At the same donor concentration, either the amounts of transport of AP-to-BL or BL-to-AP increased with increase in donor concentration and incubation time. Verapamil could significantly improve the amounts of transport of AP-to-BL. The transport of AP-to-BL and BL-to-AP depended on temperature, and there was no significant effect of pH on the transport of AP-to-BL. Magnolol could be transported through the intestinal mucosa via a passive diffusion mechanism primarily, coexisting with a carrier-mediated transport, at the same time, the efflux mechanism could be involved.

Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system.

PubMed

Zhang, Zhenhai; Cui, Changchang; Wei, Fang; Lv, Huixia

2017-08-01

The aim of this study was to develop a novel mix micelles system composing of two biocompatible copolymers of Soluplus ® and Pluronic F127 to improve the solubility, oral bioavailability of insoluble drug apigenin (AP) as model drug. The AP-loaded mixed micelles (AP-M) were prepared by ethanol thin-film hydration method. The formed optimal formulation of AP-M were provided with small size (178.5 nm) and spherical shape at ratio of 4:1 (Soluplus ® :Pluronic F127), as well as increasing solubility of to 5.61 mg/mL in water which was about 3442-fold compared to that of free AP. The entrapment efficiency and drug loading of AP-M were 95.72 and 5.32%, respectively, and a sustained release of AP-M was obtained as in vitro release study indicated. Transcellular transport study showed that the cell uptake of AP was increased in Caco-2 cell transport models. The oral bioavailability of AP-M was 4.03-fold of free AP in SD rats, indicating the mixed micelles of Soluplus ® and Pluronic F127 is an industrially feasible drug delivery system to promote insoluble drug oral absorption in the gastrointestinal tract.

Effects of 4-aminopyridine on cardiac repolarization, PR interval, and heart rate in patients with spinal cord injury.

PubMed

Isoda, Wakana C; Segal, Jack L

2003-02-01

To determine the effects of 4-aminopyridine (4-AP) on heart rate and PR, QT, and QTc intervals in patients with longstanding spinal cord injury (SCI). Randomized, active-treatment-controlled, dose level-blinded study, with allocation concealed. University-affiliated, tertiary care medical center. Sixty otherwise healthy male and female outpatients with traumatic SCI of more than 1 year's duration. Intervention. Oral administration and dose titration to tolerance of an immediate-release formulation of 4-AP. The PR interval, heart rate, QT interval, and QTc interval obtained from standard 12-lead electrocardiograms (ECGs) at baseline (before administration of 4-AP) and after 1 month of treatment were compared. The QTc intervals were derived by using Bazett's formula (equation) incorporated into standard computerized analyses of 12-lead ECG printouts. The paired t test was performed to test for the significance of differences between means and variances. No statistically significant differences were noted in heart rate or between ECG time intervals measured at baseline and after 1 month of treatment with 4-AP among all patients with SCI or between subgroups stratified by injury level (tetraplegia, paraplegia) or sex. During the 1-month period that 4-AP was administered, the heart rate and PR, QT, and QTc intervals all remained unchanged and stayed well within normal range in comparison to literature-derived control values. 4-Aminopyridine does not appear to influence the length of cardiac time intervals or heart rate and, hence, is unlikely to cause potentially life-threatening ventricular dysrrhythmias when administered long-term and taken orally in dosages of up to 30 mg/day. Specifically, cardiac repolarization (QTc interval) is unaffected in patients with SCI who continuously receive 4-AP for up to 1 month.

Short-term action potential memory and electrical restitution: A cellular computational study on the stability of cardiac repolarization under dynamic pacing

PubMed Central

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

Mechanistic Basis for Type 2 Long QT Syndrome Caused by KCNH2 Mutations that Disrupt Conserved Arginine Residue in the Voltage Sensor

PubMed Central

McBride, Christie M.; Smith, Ashley M.; Smith, Jennifer L.; Reloj, Allison R.; Velasco, Ellyn J.; Powell, Jonathan; Elayi, Claude S.; Bartos, Daniel C.; Burgess, Don E.

2013-01-01

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (IKr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing IKr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (IKv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients’ genotypes) mostly corrected the changes in IKv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing IKr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease IKr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient. PMID:23546015

Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor.

PubMed

McBride, Christie M; Smith, Ashley M; Smith, Jennifer L; Reloj, Allison R; Velasco, Ellyn J; Powell, Jonathan; Elayi, Claude S; Bartos, Daniel C; Burgess, Don E; Delisle, Brian P

2013-05-01

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (I Kr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing I Kr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (I Kv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients' genotypes) mostly corrected the changes in I Kv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing I Kr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease I Kr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.

Large vasodilatations in skeletal muscle of resting conscious dogs and their contribution to blood pressure variability

PubMed Central

Just, Armin; Schneider, Christian; Ehmke, Heimo; Kirchheim, Hartmut R

2000-01-01

Large (up to +400 %) transient (∼20 s) increases of blood flow were observed in the external iliac arteries of resting conscious dogs (n = 10) in the absence of major alerting or muscular activity. At the same time arterial pressure (AP) fellslightly while heart rate (HR) rose. The vasodilatations were resistant to atropine, ganglionic, β-adrenergic and NO-synthase inhibition, but were suppressed by spinal or general anaesthesia. Vasodilatations of similar appearance were elicited by an alerting sound; these were abolished by atropine. The spontaneous vasodilatations occurred simultaneously and their magnitudes were well correlated between both legs, but were not correlated to the amount of concomitant activation of the surface electromyogram. The duration of this activation almost never outlasted 10 s. The reactive hyperaemia observed after a total occlusion of the artery even for 16 s was not large enough to explain the size of the spontaneous vasodilatations. Occlusion during peak flow of the vasodilatations did not affect the size of the reactive hyperaemia. Spectral analysis made separately for data segments with and without vasodilatation revealed that the vasodilatations substantially enhanced the variability of AP and HR at frequencies below ∼0.1 Hz. In conclusion, large coordinated skeletal muscle vasodilatations were identified in resting conscious dogs, which are initiated neurally, but not by sympathetic-cholinergic or nitroxidergic fibres and which do not show any clear correlation to muscular contraction. The vasodilatations substantially affect the regulation of skeletal muscle blood flow and explain a significant portion of AP and HR variability. PMID:10990545

ATP6AP2 over-expression causes morphological alterations in the hippocampus and in hippocampus-related behaviour.

PubMed

Bracke, A; Schäfer, S; von Bohlen Und Halbach, V; Klempin, F; Bente, K; Bracke, K; Staar, D; van den Brandt, J; Harzsch, S; Bader, M; Wenzel, U O; Peters, J; von Bohlen Und Halbach, O

2018-02-23

The (pro)renin receptor [(P)RR], also known as ATP6AP2 [ATPase 6 accessory protein 2], is highly expressed in the brain. ATP6AP2 plays a role in early brain development, adult hippocampal neurogenesis and in cognitive functions. Lack of ATP6AP2 has deleterious effects, and mutations of ATP6AP2 in humans are associated with, e.g. X-linked intellectual disability. However, little is known about the effects of over-expression of ATP6AP2 in the adult brain. We hypothesized that mice over-expressing ATP6AP2 in the brain might exhibit altered neuroanatomical features and behavioural responses. To this end, we investigated heterozygous transgenic female mice and confirmed increased levels of ATP6AP2 in the brain. Our data show that over-expression of ATP6AP2 does not affect adult hippocampal neurogenesis, exercise-induced cell proliferation, or dendritic spine densities in the hippocampus. Only a reduced ventricular volume on the gross morphological level was found. However, ATP6AP2 over-expressing mice displayed altered exploratory behaviour with respect to the hole-board and novel object recognition tests. Moreover, primary adult hippocampal neural stem cells over-expressing ATP6AP2 exhibit a faster cell cycle progression and increased cell proliferation. Together, in contrast to the known deleterious effects of ATP6AP2 depletion, a moderate over-expression results in moderate behavioural changes and affects cell proliferation rate in vitro.

Astragalus polysaccharides inhibits PCV2 replication by inhibiting oxidative stress and blocking NF-κB pathway.

PubMed

Xue, Hongxia; Gan, Fang; Zhang, Zheqian; Hu, Junfa; Chen, Xingxiang; Huang, Kehe

2015-11-01

Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated disease (PCVAD). Astragalus polysaccharide (APS), as one kind of biological macromolecule extracted from Astragalus, has antiviral activities. This study was undertaken to explore the effect of APS on PCV2 replication in vitro and the underlying mechanisms. Our results showed that adding APS before PCV2 infection decreased significantly PCV2 DNA copies, the number of infected cells, MDA level, ROS level and NF-κB activation in PK15 cells and increased significantly GSH contents and SOD activity compared to control without APS. Oxidative stress induced by BSO could eliminate the effect of PCV2 replication inhibition by APS. LPS, as a NF-κB activator, could attenuate the effect of PCV2 replication inhibition by APS. BAY 11-7082, as a NF-κB inhibitor, could increase the effect of PCV2 replication inhibition by APS. In conclusion, APS inhibits PCV2 replication by decreasing oxidative stress and the activation of NF-κB signaling pathway, which suggests that APS might be employed for the prevention of PCV2 infection. Copyright © 2015 Elsevier B.V. All rights reserved.

Risk Factor Differences in Calcified and Non-Calcified Aortic Plaque: The Framingham Heart Study

PubMed Central

Chuang, Michael L.; Gona, Philimon; Oyama-Manabe, Noriko; Manders, Emily S.; Salton, Carol J.; Hoffmann, Udo; Manning, Warren J.; O'Donnell, Christopher J.

2014-01-01

Objective Determine the prevalence and risk factor (RF) correlates of aortic plaque (AP) detected by cardiovascular magnetic resonance (CMR), which mainly shows noncalcified plaques, and by noncontrast computed tomography (CT), which best depicts calcified plaques, in community-dwelling adults. Approach and Results 1016 Framingham Offspring cohort members (64±9y, 474 men) underwent CMR and CT of the aorta. Potential RFs for AP (age; sex; BMI; blood pressure; LDL and HDL cholesterol; fasting glucose; C-reactive protein; prevalent hypertension, diabetes, smoking; use of antihypertensive, diabetes or lipid-lowering drugs) were compared between participants with zero versus nonzero AP by CMR and by CT. Candidate RFs attaining p<0.05 for difference with either imaging modality were entered into multivariable logistic regression models adjusting for age, sex and other RFs. Odds ratios were calculated for modality-specific prevalence of AP. Associations between RFs and continuous measures of AP were assessed using Tobit regression. Prevalences of CMR and CT AP were 49% and 82% respectively. AP burdens by CMR and CT were correlated, r=0.28, p<0.0001. Increasing age and smoking were associated with prevalent AP by both CMR and CT. Additionally, prevalent AP by CMR was associated with female sex and fasting glucose, prevalent AP by CT with hypertension treatment and with adverse lipid profile. Conclusions AP by CMR and CT are both associated with smoking and increasing age, but other risk factors differ between calcified and noncalcified AP. The relative predictive value of AP detected by CMR versus by CT for incident cardiovascular events remains to be determined. PMID:24833796

In vivo levels of diadenosine tetraphosphate and adenosine tetraphospho-guanosine in Physarum polycephalum during the cell cycle and oxidative stress.

PubMed Central

Garrison, P N; Mathis, S A; Barnes, L D

1986-01-01

Cellular levels of diadenosine tetraphosphate (Ap4A) and adenosine tetraphospho-guanosine (Ap4G) were specifically measured during the cell cycle of Physarum polycephalum by a high-pressure liquid chromatographic method. Ap4A was also measured indirectly by a coupled phosphodiesterase-luciferase assay. No cell cycle-specific changes in either Ap4A or Ap4G were detected in experiments involving different methods of assay, different strains of P. polycephalum, or different methods of fixation of macroplasmodia. Our results on Ap4A are in contrast with those reported previously (C. Weinmann-Dorsch, G. Pierron, R. Wick, H. Sauer, and F. Grummt, Exp. Cell Res. 155:171-177, 1984). Weinmann-Dorsch et al. reported an 8- to 30-fold increase in Ap4A in early S phase in P. polycephalum, as measured by the phosphodiesterase-luciferase assay. We also measured levels of Ap4A, Ap4G, and ATP in macroplasmodia treated with 0.1 mM dinitrophenol. Ap4A and Ap4G transiently increased three- to sevenfold after 1 h and then decreased concomitantly with an 80% decrease in the level of ATP after 2 h in the presence of dinitrophenol. These results do not support the hypothesis that Ap4A is a positive pleiotypic activator that modulates DNA replication, but they are consistent with the hypothesis proposed for procaryotes that Ap4A and Ap4G are signal nucleotides or alarmones of oxidative stress (B.R. Bochner, P.C. Lee, S.W. Wilson, C.W. Cutler, and B.N. Ames, Cell 37:225-232, 1984). PMID:3785160

Comparison of Spectral and Scintillation Properties of LuAP:Ce and LuAP:Ce,Sc Single Crystals

NASA Astrophysics Data System (ADS)

Petrosyan, Ashot G.; Derdzyan, Marina; Ovanesyan, Karine; Shirinyan, Grigori; Lecoq, Paul; Auffray, Etiennette; Kronberger, Matthias; Frisch, Benjamin; Pedrini, Christian; Dujardin, Christophe

2009-10-01

Scintillation properties of LuAP:Ce and LuAP:Ce,Sc crystal series were studied under excitation by gamma-rays from a 137Cs source. Both series demonstrated comparable optical quality in terms of underlying absorption at 260 nm, slope of the optical edge and transmission in the range of emission. The light yield of LuAP:Ce crystals measured in 0.2 cm times 0.2 cm times 0.8 cm pixels increases linearly with the Ce concentration reaching at 0.58 at. % 6448 plusmn 322 ph/MeV and 9911 plusmn 496 ph/MeV in the long and in the short directions respectively (the light yield ratio is 65%) and shows no sign of light saturation. The energy resolution is found to depend, among other factors, on the uniformity of Ce concentration within the pixels and is improved to 7.1 plusmn 0.4% (I = 0.2 cm), 9.5 plusmn 0.5% (I = 0.8 cm). Intentional co-doping with Sc + ions was tested and resulted in increase of the Ce distribution coefficient to about 0.3. This enabled to increase the concentration of Ce in LuAP:Ce,Sc crystals up to 0.7 at. %, while conserving high optical quality. In contrast to LuAP:Ce, the light yield in LuAP:Ce,Sc crystals does not increase with Ce concentration, the photo peak being gradually suppressed. The involved mechanisms are discussed basing on measurements of the unit cell volumes, Ce concentration uniformity, x-ray rocking spectra, absorption spectra of pure and variously doped LuAP crystals, and emission spectra under different excitations.

Genome-Wide Analysis of the AP2/ERF Gene Family in Physic Nut and Overexpression of the JcERF011 Gene in Rice Increased Its Sensitivity to Salinity Stress

PubMed Central

Tang, Yuehui; Qin, Shanshan; Guo, Yali; Chen, Yanbo; Wu, Pingzhi; Chen, Yaping; Li, Meiru; Jiang, Huawu; Wu, Guojiang

2016-01-01

The AP2/ERF transcription factors play crucial roles in plant growth, development and responses to biotic and abiotic stresses. A total of 119 AP2/ERF genes (JcAP2/ERFs) have been identified in the physic nut genome; they include 16 AP2, 4 RAV, 1 Soloist, and 98 ERF genes. Phylogenetic analysis indicated that physic nut AP2 genes could be divided into 3 subgroups, while ERF genes could be classed into 11 groups or 43 subgroups. The AP2/ERF genes are non-randomly distributed across the 11 linkage groups of the physic nut genome and retain many duplicates which arose from ancient duplication events. The expression patterns of several JcAP2/ERF duplicates in the physic nut showed differences among four tissues (root, stem, leaf, and seed), and 38 JcAP2/ERF genes responded to at least one abiotic stressor (drought, salinity, phosphate starvation, and nitrogen starvation) in leaves and/or roots according to analysis of digital gene expression tag data. The expression of JcERF011 was downregulated by salinity stress in physic nut roots. Overexpression of the JcERF011 gene in rice plants increased its sensitivity to salinity stress. The increased expression levels of several salt tolerance-related genes were impaired in the JcERF011-overexpressing plants under salinity stress. PMID:26943337

Correlating the Effects of Antimicrobial Preservatives on Conformational Stability, Aggregation Propensity, and Backbone Flexibility of an IgG1 mAb.

PubMed

Arora, Jayant; Joshi, Sangeeta B; Middaugh, C Russell; Weis, David D; Volkin, David B

2017-06-01

Multidose formulations of biotherapeutics, which offer better dosage management and reduced production costs, require the addition of antimicrobial preservatives (APs). APs have been shown, however, to decrease protein stability in solution and cause protein aggregation. In this report, the effect of 4 APs, m-cresol, phenol, phenoxyethanol, and benzyl alcohol on conformational stability, aggregation propensity, and backbone flexibility of an IgG1 mAb, mAb-4, is investigated. Compared with no preservative control, each of the APs decreased the conformational stability of mAb-4 as measured by differential scanning calorimetry and extrinsic fluorescence spectroscopy. The addition of APs resulted in increased monomer loss and aggregate accumulation at 50°C over 28 days, as monitored by size-exclusion chromatography. The extent of conformational destabilization and protein aggregation of mAb-4 induced by APs followed their calculated octanol-water partition coefficients. Increases in backbone flexibility, as measured by hydrogen exchange, of a region located in the C H 2 domain of the mAb (heavy chain 237-254) in the presence of APs also correlated with hydrophobicity. Based on these results, the destabilizing effect of APs on mAb-4 correlates with the increased hydrophobicity of the APs and their ability to enhance the local backbone flexibility of an aggregation hot spot within the C H 2 domain of the mAb. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Genome-Wide Analysis of the AP2/ERF Gene Family in Physic Nut and Overexpression of the JcERF011 Gene in Rice Increased Its Sensitivity to Salinity Stress.

PubMed

Tang, Yuehui; Qin, Shanshan; Guo, Yali; Chen, Yanbo; Wu, Pingzhi; Chen, Yaping; Li, Meiru; Jiang, Huawu; Wu, Guojiang

2016-01-01

The AP2/ERF transcription factors play crucial roles in plant growth, development and responses to biotic and abiotic stresses. A total of 119 AP2/ERF genes (JcAP2/ERFs) have been identified in the physic nut genome; they include 16 AP2, 4 RAV, 1 Soloist, and 98 ERF genes. Phylogenetic analysis indicated that physic nut AP2 genes could be divided into 3 subgroups, while ERF genes could be classed into 11 groups or 43 subgroups. The AP2/ERF genes are non-randomly distributed across the 11 linkage groups of the physic nut genome and retain many duplicates which arose from ancient duplication events. The expression patterns of several JcAP2/ERF duplicates in the physic nut showed differences among four tissues (root, stem, leaf, and seed), and 38 JcAP2/ERF genes responded to at least one abiotic stressor (drought, salinity, phosphate starvation, and nitrogen starvation) in leaves and/or roots according to analysis of digital gene expression tag data. The expression of JcERF011 was downregulated by salinity stress in physic nut roots. Overexpression of the JcERF011 gene in rice plants increased its sensitivity to salinity stress. The increased expression levels of several salt tolerance-related genes were impaired in the JcERF011-overexpressing plants under salinity stress.

GM2-activator protein: a new biomarker for lung cancer.

PubMed

Potprommanee, Laddawan; Ma, Haou-Tzong; Shank, Lalida; Juan, Yi-Hsiu; Liao, Wei-Yu; Chen, Shui-Tein; Yu, Chong-Jen

2015-01-01

Effective biomarkers for early diagnosis of lung cancer are needed. A recent study demonstrated that urinary GM2-activator protein (GM2AP) level was increased in lung cancer patients. This study aims to validate the potential application of GM2AP as a biomarker for diagnosis of lung cancer. Serum and urine samples were obtained from 189 participants (133 patients for treatment naive lung cancer, 26 healthy volunteers for urine, and 30 healthy volunteers for serum). GM2AP level was detected by Western blotting and quantified using enzyme-linked immunosorbent assay (ELISA). The GM2AP expression in tumors and nontumor parts of lung tissues from 143 nonsmall cell lung cancers was detected by immunohistochemical stains. There was an 8.11 ± 1.36 folds increase in urine and a 5.41 ± 0.73 folds increase in serum level of GM2AP in lung cancer patients compared with healthy volunteers (p < 0.0001), achieving a 0.89 AUC value in urine and 0.90 AUC value in serum for the receiver-operating characteristic curves. Both serum and urine levels of GM2AP correlated significantly with pathology stages (urine, p = 0.009; serum, p < 0.0001). Using immunohistochemical, positive expression of GM2AP was found at 83.9% of nonsmall cell lung cancers patients and none in normal tissue. The GM2AP expression was significantly correlated with pathology stage (p = 0.0001). Patients with higher GM2AP expression had shorter overall survival (p = 0.045) and disease-free survival (p = 0.049) than lower GM2AP expression. Moreover, the multivariate analysis suggested GM2AP as an independent predictors of disease-free survival and overall survival. Our study demonstrates that GM2AP might serve as potential diagnostic and prognostic biomarkers in patients with lung cancer.

Evaluation of the prognostic value of neutrophil to lymphocyte ratio in patients with hypertriglyceridemia-induced acute pancreatitis.

PubMed

Wang, Yuchen; Fuentes, Harry E; Attar, Bashar M; Jaiswal, Palash; Demetria, Melchor

Recent studies attribute promising prognostic values to various inflammatory biomarkers in acute pancreatitis, including the following: the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and red cell distribution width (RDW). We aimed to determine the performance of these biomarkers for detecting disease severity in patients with hypertriglyceridemia-induced acute pancreatitis (HTG-AP). We retrospectively reviewed 110 patients with HTG-AP and compared the NLR, PLR, and RDW in different severity groups. We performed receiver-operating characteristic (ROC) analysis to identify the optimal cut-off value for NLR to predict severe AP. NLR was significantly higher in patients with severe AP than mild and moderately severe AP (14.6 vs. 6.9, p < 0.001), and higher with organ failure upon presentation (9.1 vs. 7.1, p = 0.026). After dichotomization by the optimal cut-off value of 10 as determined by the ROC curve, the high-NLR group had a significantly longer length of stay (9.1 vs. 6.6 days, p = 0.001), duration of nil per os (4.9 vs. 3.7 days, p = 0.007), and higher rates of complications, including systemic inflammatory response syndrome (81.5% vs. 44.6%, p = 0.001) and persistent acute kidney injury (25.9% vs. 3.6%, p < 0.001). High NLR independently predicted severe acute pancreatitis in multivariate analysis (Odds ratio 6.71, p = 0.019). NLR represents an inexpensive, readily available test with a promising value to predict disease severity in HTG-AP. Among the three inflammatory biomarkers, NLR has the highest discriminatory capacity for severe HTG-AP, with an optimal cut-off value of 10. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Apelin-13 increased food intake with serum ghrelin and leptin levels in male rats.

PubMed

Saral, S; Alkanat, M; Sumer, A; Canpolat, S

2018-01-01

In this study, we aimed to explain the role of apelin-13 on body weight, food and water intake with serum leptin, ghrelin, neuropeptid Y (NPY) and peptid YY (PYY) levels in male rat. Thirty-two Sprague-Dawley male rats were used for the study. The rats were injected SP (0.9 %) intraperitoneally (i.p) in the control group and 30 (AP30), 100 (AP100) and 300 (AP300) µg/kg apelin-13 in the study groups, respectively, 10 min before the transition to dark period, for 10 days. During the experimental period, with light and dark periods of food and water intake, body weights were recorded in rats. Rats were euthanized and serum samples were obtained. In serum samples leptin, ghrelin, NPY and PYY levels were measured with specific ELISA kit. Apelin-13 was increased body weights in all three (AP30, AP100 and AP300) groups compared with the control group. AP100 and AP300 groups had increased food intake in the dark and the cumulative period, but in the light period food intake values were not significantly increased (p > 0.05). As for the value of water intake, compared with the control group, all dose of apelin-13 increased water intake during the dark and the cumulative period. There was no significant change in water intake in the light period. On the other hand, compared with the control group, serum leptin levels were found to increase in the groups administered 100 and 300 µg/kg of apelin-13 (p < 0.05). Ghrelin levels were found high in all groups treated with apelin-13. Serum levels of NPY decreased only in the 300 µg/kg apelin-13 treated group (p 0.05). Apelin-13 increases body weight in rats as well as food and water intake (dark and cumulative period). Additionally, ghrelin can mediate the orexigenic effect of apelin-13 in the regulation of food intake (Fig. 4, Ref. 37).

Antipsychotic-Induced Changes in Blood Levels of Leptin in Schizophrenia: A Meta-Analysis

PubMed Central

Potvin, Stéphane; Zhornitsky, Simon; Stip, Emmanuel

2015-01-01

Objectives: Weight gain is a major side effect of antipsychotics (APs), which contributes to poor treatment adherence and significant morbidity. The mechanisms involved in AP-induced weight gain are incompletely understood. Recently, it has been proposed that changes in leptin, an cadipocyte-derived hormone exerting anorexigenic effects, may be involved in AP-induced weight gain. Thus far, studies on leptin changes during AP treatment have produced inconsistent results, prompting our group to perform a meta-analysis. Method: A search of the literature was performed using PubMed and Embase. Studies were included only if reporting peripheral levels of leptin before and after AP treatment in schizophrenia. Effect size estimates were calculated with Hedges g and were aggregated using a random effects model as results were heterogeneous (P < 0.10). Meta-regression analyses were performed using study length and changes in body mass index (BMI) as moderator variables. Results: Twenty-eight studies were retrieved, including 39 comparisons. A moderate and positive effect size was observed across studies. Olanzapine, clozapine, and quetiapine produced moderate leptin elevations, whereas haloperidol and risperidone were associated with small (nonsignificant) leptin changes. Across studies, BMI changes were significantly associated with increases in leptin levels. There was no effect of sex on AP-induced changes in leptin. Conclusions: A physiological role of leptin in AP-induced weight gain is supported because the most significant leptin increases were observed with APs inducing the most weight gain and because of the observed association between leptin increases and BMI changes. The overall increase in leptin levels suggests that leptin acts as a negative feedback signal in the event of fat increase. PMID:25886677

Diadenosine tetraphosphate (Ap4A) induces a diabetogenic situation: its impact on blood glucose, plasma insulin, gluconeogenesis, glucose uptake and GLUT-4 transporters.

PubMed

Verspohl, E J; Hohmeier, N; Lempka, M

2003-12-01

Diadenosine polyphosphates such as Ap4A are physiologically released compounds for which both receptors as well as a role as second messengers for influencing insulin release have been shown. So far little is known about their pathophysiological impact on diabetes with respect to blood glucose and plasma insulin, glucose production via gluconeogenesis, glucose uptake and GLUT-4 expression. Rats given an intravenous bolus of Ap4A (0.75 mg/kg) developed a rapid and dramatic increase in blood glucose. Plasma insulin was only transiently increased (for 4 min), but did not follow the normally stimulatory effect of the elevated blood glucose. A bolus of 25 microg Ap4A quickly increased glucose release from perfused rat liver. Glucose uptake was reduced in 3T3 adipocytes. Reduced amounts of translocated GLUT-4 were found in 3T3 cell membranes incubated with 10 microM Ap4A. Thus, Ap4A itself induces a diabetic situation which is likely to be mediated by an increase in gluconeogenesis and/or an insulin resistance caused by a decrease in GLUT-4 and an attenuation of glucose uptake.

APS Education and Diversity Efforts

NASA Astrophysics Data System (ADS)

Prestridge, Katherine; Hodapp, Theodore

2015-11-01

American Physical Society (APS) has a wide range of education and diversity programs and activities, including programs that improve physics education, increase diversity, provide outreach to the public, and impact public policy. We present the latest programs spearheaded by the Committee on the Status of Women in Physics (CSWP), with highlights from other diversity and education efforts. The CSWP is working to increase the fraction of women in physics, understand and implement solutions for gender-specific issues, enhance professional development opportunities for women in physics, and remedy issues that impact gender inequality in physics. The Conferences for Undergraduate Women in Physics, Professional Skills Development Workshops, and our new Professional Skills program for students and postdocs are all working towards meeting these goals. The CSWP also has site visit and conversation visit programs, where department chairs request that the APS assess the climate for women in their departments or facilitate climate discussions. APS also has two significant programs to increase participation by underrepresented minorities (URM). The newest program, the APS National Mentoring Community, is working to provide mentoring to URM undergraduates, and the APS Bridge Program is an established effort that is dramatically increasing the number of URM PhDs in physics.

Using a Classroom Response System to Improve Multiple-Choice Performance in AP[R] Physics

ERIC Educational Resources Information Center

Bertrand, Peggy

2009-01-01

Participation in rigorous high school courses such as Advanced Placement (AP[R]) Physics increases the likelihood of college success, especially for students who are traditionally underserved. Tackling difficult multiple-choice exams should be part of any AP program because well-constructed multiple-choice questions, such as those on AP exams and…

Incidence and mortality of acute and chronic pancreatitis in the Netherlands: a nationwide record-linked cohort study for the years 1995-2005.

PubMed

Spanier, B W Marcel; Bruno, Marco J; Dijkgraaf, Marcel G W

2013-05-28

To analyze trends in incidence and mortality of acute pancreatitis (AP) and chronic pancreatitis (CP) in the Netherlands and for international standard populations. A nationwide cohort is identified through record linkage of hospital data for AP and CP, accumulated from three nationwide Dutch registries: the hospital discharge register, the population register, and the death certificate register. Sex- and age-group specific incidence rates of AP and CP are defined for the period 2000-2005 and mortality rates of AP and CP for the period 1995-2005. Additionally, incidence and mortality rates over time are reported for Dutch and international (European and World Health Organization) standard populations. Incidence of AP per 100000 persons per year increased between 2000 and 2005 from 13.2 (95%CI: 12.6-13.8) to 14.7 (95%CI: 14.1-15.3). Incidence of AP for males increased from 13.8 (95%CI: 12.9-14.7) to 15.2 (95%CI: 14.3-16.1), for females from 12.7 (95%CI: 11.9-13.5) to 14.2 (95%CI: 13.4-15.1). Irregular patterns over time emerged for CP. Overall mean incidence per 100000 persons per year was 1.77, for males 2.16, and for females 1.4. Mortality for AP fluctuated during 1995-2005 between 6.9 and 11.7 per million persons per year and was almost similar for males and females. Concerning CP, mortality for males fluctuated between 1.1 (95%CI: 0.6-2.3) and 4.0 (95%CI: 2.8-5.8), for females between 0.7 (95%CI: 0.3-1.6) and 2.0 (95%CI: 1.2-3.2). Incidence and mortality of AP and CP increased markedly with age. Standardized rates were lowest for World Health Organization standard population. Incidence of AP steadily increased while incidence of CP fluctuated. Mortality for both AP and CP remained fairly stable. Patient burden and health care costs probably will increase because of an ageing Dutch population.

Diadenosine tetraphosphate (Ap4A) and triphosphate (Ap3A) signaling of human sperm motility.

PubMed

Chan, P J; Su, B C; Tredway, D R

1991-01-01

The ubiquitous dinucleotide polyphosphate, diadenosine tetraphosphate (Ap4A), has been shown to be a signal molecule for DNA replication in mammalian cells. In this study, Ap4A and a related compound, diadenosine triphosphate (Ap3A), were tested for possible signaling functions in human spermatozoa. A computerized automated semen analyzer was used to detect changes in spermatozoa motility parameters. Cryopreserved-thawed donor spermatozoa were washed and incubated in 0.1 mM Ap4A, 0.1 mM Ap3A, or control medium. The data indicated that both Ap4A and Ap3A decreased the percentage of motile spermatozoa after 4 or more hours of incubation in vitro. The two dinucleotide polyphosphates caused an increase in the amplitude of lateral spermatozoa head displacement parameter only at the start of incubation. The other spermatozoa kinematic parameters were unaffected. No opposing ying-yang dual actions of Ap4A to Ap3A were seen. From the results, Ap4A and Ap3A were observed to be potential inhibitory signals of spermatozoa motility after prolonged exposure.

Anti-Obesity and Anti-Diabetic Effects of Acacia Polyphenol in Obese Diabetic KKAy Mice Fed High-Fat Diet

PubMed Central

Ikarashi, Nobutomo; Toda, Takahiro; Okaniwa, Takehiro; Ito, Kiyomi; Ochiai, Wataru; Sugiyama, Kiyoshi

2011-01-01

Acacia polyphenol (AP) extracted from the bark of the black wattle tree (Acacia meansii) is rich in unique catechin-like flavan-3-ols, such as robinetinidol and fisetinidol. The present study investigated the anti-obesity/anti-diabetic effects of AP using obese diabetic KKAy mice. KKAy mice received either normal diet, high-fat diet or high-fat diet with additional AP for 7 weeks. After the end of administration, body weight, plasma glucose and insulin were measured. Furthermore, mRNA and protein expression of obesity/diabetic suppression-related genes were measured in skeletal muscle, liver and white adipose tissue. As a result, compared to the high-fat diet group, increases in body weight, plasma glucose and insulin were significantly suppressed for AP groups. Furthermore, compared to the high-fat diet group, mRNA expression of energy expenditure-related genes (PPARα, PPARδ, CPT1, ACO and UCP3) was significantly higher for AP groups in skeletal muscle. Protein expressions of CPT1, ACO and UCP3 for AP groups were also significantly higher when compared to the high-fat diet group. Moreover, AP lowered the expression of fat acid synthesis-related genes (SREBP-1c, ACC and FAS) in the liver. AP also increased mRNA expression of adiponectin and decreased expression of TNF-α in white adipose tissue. In conclusion, the anti-obesity actions of AP are considered attributable to increased expression of energy expenditure-related genes in skeletal muscle, and decreased fatty acid synthesis and fat intake in the liver. These results suggest that AP is expected to be a useful plant extract for alleviating metabolic syndrome. PMID:21799697

Acute pancreatitis with gradient echo T2*-weighted magnetic resonance imaging

PubMed Central

Tang, Meng Yue; Chen, Tian Wu; Huang, Xiao Hua; Li, Xing Hui; Wang, Si Yue; Liu, Nian

2016-01-01

Background To study gradient recalled echo (GRE) T2*-weighted imaging (T2*WI) for normal pancreas and acute pancreatitis (AP). Methods Fifty-one patients without any pancreatic disorders (control group) and 117 patients with AP were recruited. T2* values derived from T2*WI of the pancreas were measured for the two groups. The severity of AP was graded by the magnetic resonance severity index (MRSI) and the Acute Physiology and Chronic Healthy Evaluation II (APACHE II) scoring system. Logistic regression was used to analyze the relationship between the T2* values and AP severity. The usefulness of the T2* value for diagnosing AP and the relationship between the T2* values and the severity of AP were analyzed. Results On GRE-T2*WI, the normal pancreas showed a well-marinated and consistently homogeneous isointensity. Edematous AP, as well as the non-necrotic area in necrotizing AP, showed ill-defined but homogeneous signal intensity. AP with pancreatic hemorrhage showed a decreased T2* value and a signal loss on the signal decay curve. The T2* value of pancreas in the AP group was higher than that of the control group (t=−8.20, P<0.05). The T2* value tended to increase along with the increase in MRSI scores but not with the APACHE II scores (P>0.05). AP was associated with a one standard deviation increment in the T2* value (OR =1.37; 95% CI: 1.216–1.532). Conclusions T2*WI demonstrates a few characteristics of the normal pancreas and AP, which could potentially be helpful for detecting hemorrhage, and contributes to diagnosing AP and its severity. PMID:27190768

Risk factor differences in calcified and noncalcified aortic plaque: the Framingham Heart Study.

PubMed

Chuang, Michael L; Gona, Philimon; Oyama-Manabe, Noriko; Manders, Emily S; Salton, Carol J; Hoffmann, Udo; Manning, Warren J; O'Donnell, Christopher J

2014-07-01

The objective of this study was to determine the prevalence and risk factor (RF) correlates of aortic plaque (AP) detected by cardiovascular magnetic resonance (CMR), which mainly shows noncalcified plaques, and by noncontrast computed tomography (CT), which best depicts calcified plaques, in community-dwelling adults. A total of 1016 Framingham Heart Study Offspring cohort members (64 ± 9 years; 474 men) underwent CMR and CT of the aorta. Potential RFs for AP (age; sex; body mass index; blood pressure; low-density lipoprotein and high-density lipoprotein cholesterol; fasting glucose; C-reactive protein; prevalent hypertension, diabetes mellitus, smoking; use of antihypertensive, diabetes mellitus, or lipid-lowering drugs) were compared between participants, with zero versus nonzero AP by CMR and by CT. Candidate RFs attaining P<0.05 for difference with either imaging modality were entered into multivariable logistic regression models adjusting for age, sex, and other RFs. Odds ratios were calculated for modality-specific prevalence of AP. Associations between RFs and continuous measures of AP were assessed using Tobit regression. Prevalence of CMR and CT AP was 49% and 82%, respectively. AP burdens by CMR and CT were correlated, r=0.28, P<0.0001. Increasing age and smoking were associated with prevalent AP by both CMR and CT. Additionally, prevalent AP by CMR was associated with female sex and fasting glucose and prevalent AP by CT with hypertension treatment and adverse lipid profile. AP by CMR and CT are both associated with smoking and increasing age, but other RFs differ between calcified and noncalcified AP. The relative predictive value of AP detected by CMR versus by CT for incident cardiovascular events remains to be determined. © 2014 American Heart Association, Inc.

In vitro and in vivo antioxidant potential of milks, yoghurts, fermented milks and cheeses: a narrative review of evidence.

PubMed

Fardet, Anthony; Rock, Edmond

2018-06-01

The antioxidant potential (AP) is an important nutritional property of foods, as increased oxidative stress is involved in most diet-related chronic diseases. In dairy products, the protein fraction contains antioxidant activity, especially casein. Other antioxidants include: antioxidant enzymes; lactoferrin; conjugated linoleic acid; coenzyme Q10; vitamins C, E, A and D3; equol; uric acid; carotenoids; and mineral activators of antioxidant enzymes. The AP of dairy products has been extensively studied in vitro, with few studies in animals and human subjects. Available in vivo studies greatly differ in their design and objectives. Overall, on a 100 g fresh weight-basis, AP of dairy products is close to that of grain-based foods and vegetable or fruit juices. Among dairy products, cheeses present the highest AP due to their higher protein content. AP of milk increases during digestion by up to 2·5 times because of released antioxidant peptides. AP of casein is linked to specific amino acids, whereas β-lactoglobulin thiol groups play a major role in the AP of whey. Thermal treatments such as ultra-high temperature processing have no clear effect on the AP of milk. Raw fat-rich milks have higher AP than less fat-rich milk, because of lipophilic antioxidants. Probiotic yoghurts and fermented milks have higher AP than conventional yoghurt and milk because proteolysis by probiotics releases antioxidant peptides. Among the probiotics, Lactobacillus casei/acidophilus leads to the highest AP. The data are insufficient for cheese, but fermentation-based changes appear to make a positive impact on AP. In conclusion, AP might participate in the reported dairy product-protective effects against some chronic diseases.

Tissue-nonspecific alkaline phosphatase is activated in enterocytes by oxidative stress via changes in glycosylation.

PubMed

López-Posadas, Rocío; González, Raquel; Ballester, Isabel; Martínez-Moya, Patricia; Romero-Calvo, Isabel; Suárez, María Dolores; Zarzuelo, Antonio; Martínez-Augustin, Olga; Sánchez de Medina, Fermín

2011-02-01

Intestinal inflammation produces an induction of alkaline phosphatase (AP) activity that is attributable in part to augmented expression, accompanied by a change in isoform, in epithelial cells. This study focuses on induction of AP in intestinal epithelial cells in vitro. Treatment with the oxidants H2O2, monochloramine, or tButOOH increases AP activity in vitro in Caco-2, HT29, and IEC18 cells. We selected IEC18 cells for further testing. Basal AP activity in IEC18 cells is of the tissue-nonspecific (bone-liver-kidney) type, as indicated by Northern and Western blot analysis. Oxidative stress augments AP activity and the sensitivity of the enzyme to levamisole, homoarginine, and heat in IEC18 cells. Increased immunoreactivity to tissue-nonspecific AP antibodies suggests an isoform shift from liver to either kidney or bone type. This effect occurs without changes at the mRNA level and is sensitive to tunicamycin, an inhibitor of N-glycosylation, and neuraminidase digestion. Saponin and deoxycholate produce similar effects to oxidants. Butyrate but not proinflammatory cytokines or LPS can induce a similar effect but without toxicity. The AP increase is not prevented by modulators of the MAPK, NF-κB, calcium, and cyclic adenosine monophosphate (cAMP) pathways, and is actually enhanced by actinomycin D via higher cell stress. Oxidative stress causes a distinct increase in enterocyte AP activity together with cell toxicity via changes in the glycosylation of the enzyme that correspond to a shift in isotype within the tissue-nonspecific paradigm. We speculate that this may have physiological implication for gut defense.

Risk factors for pancreatitis in older women: the Iowa Women's Health Study.

PubMed

Prizment, Anna E; Jensen, Eric H; Hopper, Anne M; Virnig, Beth A; Anderson, Kristin E

2015-07-01

Pancreatitis-an inflammation of pancreas-is a severe and costly disease. Although many risk factors for pancreatitis are known, many pancreatitis cases, especially in elderly women, are of unknown etiology. Risk factors for acute pancreatitis (AP) and chronic pancreatitis (CP) were assessed in a prospective cohort (n = 36,436 women, aged ≥ 65 years). Exposures were self-reported at baseline. Pancreatitis was ascertained by linkage to Medicare claims (1986-2004) categorized by a physician as follows: "AP", one AP episode (n = 511) or "CP", 2+ AP or 1+ CP episodes (n = 149). Multivariable odds ratios (ORs) and 95% confidence intervals for AP and CP were calculated using multinomial logistic regression. Alcohol use was not associated with AP or CP. Heavy smoking (40+ vs. 0 pack-years) was associated with a twofold increased OR for CP. For body mass index greater than or equal to 30 versus less than 25 kg/m(2), the ORs were 1.35 (1.07-1.70) for AP (P trend = .009) and 0.59 (0.37-0.94) for CP (P trend = .01). ORs for AP and CP were increased for hormone replacement therapy use, heart disease, and hypertension. There were positive significant associations between protein and total fat intake for CP and AP. We identified factors associated with AP and CP that may be specific to older women. Copyright © 2015 Elsevier Inc. All rights reserved.

Antiphospholipid syndrome: an evolving story.

PubMed

Robertson, Beverley; Greaves, Mike

2006-07-01

Antiphospholipid Syndrome (APS) is a form of immune mediated thrombophilia, presenting as recurrent thrombotic events and pregnancy morbidity, in association with positive laboratory tests for antiphospholipid antibodies (APA) in the form of Lupus Anticoagulant (LA) or anticardiolipin antibodies(ACA). Insights into the pathophysiology of the condition suggest that some antibodies are prothrombotic in vivo, and that the mechanism of thrombosis is likely to be multifactorial. APS has a broad spectrum of clinical presentations, and the laboratory diagnosis can be difficult due to heterogeneity of APAs and poor standardisation of laboratory tests. Anticoagulation is the mainstay of the management of the thrombotic and obstetric complications of APS. The risk of recurrent thrombosis appears to be high, and the duration and intensity of therapy remains controversial. Randomised controlled trials have shown that standard intensity anticoagulation is adequate in most cases of venous thrombosis. Further trials are required to establish whether high intensity coagulation is of benefit in recurrent or arterial thrombosis. The optimal management of recurrent fetal loss is debated and large studies are required to establish a clear benefit of heparin and aspirin over aspirin alone or supportive care.

Accession-dependent action potentials in Arabidopsis.

PubMed

Favre, Patrick; Greppin, Hubert; Degli Agosti, Robert

2011-05-01

Plant excitability, as measured by the appearance and circulation of action potentials (APs) after biotic and abiotic stress treatments, is a far lesser and more versatile phenomenon than in animals. To examine the genetic basis of plant excitability we used different Arabidopsis thaliana accessions. APs were induced by wounding (W) with a subsequent deposition (D) of 5μL of 1M KCl onto adult leaves. This treatment elicited transient voltage responses (APs) that were detected by 2 extracellular electrodes placed at a distance from the wounding location over an experimental time of 150min. The first electrode (e1) was placed at the end of the petiole and the beginning of the leaf, and the second (e2) electrode was placed on the petiole near the center of the rosette. All accessions (Columbia (Col), Wassilewskija (Ws) and Landsberg erecta (Ler)) responded to the W & D treatment. After W & D treatment was performed on 100 plants for each accession, the number of APs ranged from 0 to 37 (median 8, total 940), 0 to 16 (median 5, total 528) and 0 to 18 (median 2, total 296) in Col, Ws and Ler, respectively. Responding plants (>0 APs) showed significantly different behaviors depending on their accessions of origin (i.e., Col 91, Ws 83 and Ler 76%). Some AP characteristics, such as amplitude and speed of propagation from e1 to e2 (1.28mms(-1)), were the same for all accessions, whereas the average duration of APs was similar in Col and Ws, but different in Ler. Self-sustained oscillations were observed more frequently in Col than Ws and least often in Ler, and the mean oscillation frequency was more rapid in Col, followed by Ws, and was slowest in Ler. In general, Col was the most excitable accession, followed by Ws, and Ler was the least excitable; this corresponded well with voltage elicited action potentials. In conclusion, part of Arabidopsis excitability in AP responses is genetically pre-determined. Copyright © 2010 Elsevier GmbH. All rights reserved.

A New Class III Antiarrhythmic Drug Niferidil Prolongs Action Potentials in Guinea Pig Atrial Myocardium via Inhibition of Rapid Delayed Rectifier.

PubMed

Abramochkin, Denis V; Kuzmin, Vladislav S; Rosenshtraukh, Leonid V

2017-12-01

A new class III antiarrhythmic drug niferidil (RG-2) has been introduced as a highly effective therapy for cases of persistent atrial fibrillation, but ionic mechanisms of its action are poorly understood. In the present study, the effects of niferidil on action potential (AP) waveform and potassium currents responsible for AP repolarization were investigated in guinea pig atrial myocardium. APs were recorded with sharp glass microelectrodes in multicellular atrial preparations. Whole-cell patch-clamp technique was used to measure K + currents in isolated myocytes. In multicellular atrial preparations, 10 -8  M niferidil effectively prolonged APs by 15.2 ± 2.8% at 90% repolarization level. However, even the highest tested concentrations, 10 -6  M and 10 -5  M failed to prolong APs more than 32.5% of control duration. The estimated concentration of niferedil for half-maximal AP prolongation was 1.13 × 10 -8  M. Among the potassium currents responsible for AP repolarization phase, I K1 was found to be almost insensitive to niferidil. However, another inward rectifier, I KACh , was effectively suppressed by micromolar concentrations of niferidil with IC 50  = 9.2 × 10 -6  M. I KATP was much less sensitive to the drug with IC 50  = 2.26 × 10 -4  M. The slow component of delayed rectifier, I Ks , also demonstrated low sensitivity to niferidil-the highest used concentration, 10 -4  M, decreased peak I Ks density to 46.2 ± 5.5% of control. Unlike I Ks , the rapid component of delayed rectifier, I Kr , appeared to be extremely sensitive to niferidil. The IC 50 was 1.26 × 10 -9  M. I Kr measured in ventricular myocytes was found to be less sensitive to niferidil with IC 50  = 3.82 × 10 -8  M. Niferidil prolongs APs in guinea pig atrial myocardium via inhibition of I Kr .

A model for studying the energetics of sustained high frequency firing

PubMed Central

Morris, Catherine E.

2018-01-01

Regulating membrane potential and synaptic function contributes significantly to the energetic costs of brain signaling, but the relative costs of action potentials (APs) and synaptic transmission during high-frequency firing are unknown. The continuous high-frequency (200-600Hz) electric organ discharge (EOD) of Eigenmannia, a weakly electric fish, underlies its electrosensing and communication. EODs reflect APs fired by the muscle-derived electrocytes of the electric organ (EO). Cholinergic synapses at the excitable posterior membranes of the elongated electrocytes control AP frequency. Based on whole-fish O2 consumption, ATP demand per EOD-linked AP increases exponentially with AP frequency. Continual EOD-AP generation implies first, that ion homeostatic processes reliably counteract any dissipation of posterior membrane ENa and EK and second that high frequency synaptic activation is reliably supported. Both of these processes require energy. To facilitate an exploration of the expected energy demands of each, we modify a previous excitability model and include synaptic currents able to drive APs at frequencies as high as 600 Hz. Synaptic stimuli are modeled as pulsatile cation conductance changes, with or without a small (sustained) background conductance. Over the full species range of EOD frequencies (200–600 Hz) we calculate frequency-dependent “Na+-entry budgets” for an electrocyte AP as a surrogate for required 3Na+/2K+-ATPase activity. We find that the cost per AP of maintaining constant-amplitude APs increases nonlinearly with frequency, whereas the cost per AP for synaptic input current is essentially constant. This predicts that Na+ channel density should correlate positively with EOD frequency, whereas AChR density should be the same across fish. Importantly, calculated costs (inferred from Na+-entry through Nav and ACh channels) for electrocyte APs as frequencies rise are much less than expected from published whole-fish EOD-linked O2 consumption. For APs at increasingly high frequencies, we suggest that EOD-related costs external to electrocytes (including packaging of synaptic transmitter) substantially exceed the direct cost of electrocyte ion homeostasis. PMID:29708986

Simulation of Swap-Out Reliability For The Advance Photon Source Upgrade

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

Borland, M.

2017-06-01

The proposed upgrade of the Advanced Photon Source (APS) to a multibend-achromat lattice relies on the use of swap-out injection to accommodate the small dynamic acceptance, allow use of unusual insertion devices, and minimize collective effects at high single-bunch charge. This, combined with the short beam lifetime, will make injector reliability even more important than it is for top-up operation. We used historical data for the APS injector complex to obtain probability distributions for injector up-time and down-time durations. Using these distributions, we simulated several years of swap-out operation for the upgraded lattice for several operatingmodes. The results indicate thatmore » obtaining very high availability of beam in the storage ring will require improvements to injector reliability.« less

Functions of Adaptor Protein (AP)-3 and AP-1 in Tyrosinase Sorting from Endosomes to MelanosomesD⃞

PubMed Central

Theos, Alexander C.; Tenza, Danièle; Martina, José A.; Hurbain, Ilse; Peden, Andrew A.; Sviderskaya, Elena V.; Stewart, Abigail; Robinson, Margaret S.; Bennett, Dorothy C.; Cutler, Daniel F.; Bonifacino, Juan S.; Marks, Michael S.; Raposo, Graça

2005-01-01

Specialized cells exploit adaptor protein complexes for unique post-Golgi sorting events, providing a unique model system to specify adaptor function. Here, we show that AP-3 and AP-1 function independently in sorting of the melanocyte-specific protein tyrosinase from endosomes to the melanosome, a specialized lysosome-related organelle distinguishable from lysosomes. AP-3 and AP-1 localize in melanocytes primarily to clathrin-coated buds on tubular early endosomes near melanosomes. Both adaptors recognize the tyrosinase dileucine-based melanosome sorting signal, and tyrosinase largely colocalizes with each adaptor on endosomes. In AP-3-deficient melanocytes, tyrosinase accumulates inappropriately in vacuolar and multivesicular endosomes. Nevertheless, a substantial fraction still accumulates on melanosomes, concomitant with increased association with endosomal AP-1. Our data indicate that AP-3 and AP-1 function in partially redundant pathways to transfer tyrosinase from distinct endosomal subdomains to melanosomes and that the AP-3 pathway ensures that tyrosinase averts entrapment on internal membranes of forming multivesicular bodies. PMID:16162817

Characteristic Times of Gradual Solar Energetic Particle Events and Their Dependence on Associated Coronal Mass Ejection Properties

DTIC Science & Technology

2005-08-01

differences, including longer event durations for SEPs from quasi- Yago & Kamide (2003) have shown that the lognormal plot is parallel shocks due to the longer...Urpo, S. 1999, A&A, 348, 271 ApJ, 598, 1392 Klein, K.-L., & Trottet, G. 2001, Space Sci. Rev., 95, 215 Yago , K., & Kamide, Y. 2003, Space Weather, 1

Superresolution imaging reveals activity-dependent plasticity of axon morphology linked to changes in action potential conduction velocity.

PubMed

Chéreau, Ronan; Saraceno, G Ezequiel; Angibaud, Julie; Cattaert, Daniel; Nägerl, U Valentin

2017-02-07

Axons convey information to nearby and distant cells, and the time it takes for action potentials (APs) to reach their targets governs the timing of information transfer in neural circuits. In the unmyelinated axons of hippocampus, the conduction speed of APs depends crucially on axon diameters, which vary widely. However, it is not known whether axon diameters are dynamic and regulated by activity-dependent mechanisms. Using time-lapse superresolution microscopy in brain slices, we report that axons grow wider after high-frequency AP firing: synaptic boutons undergo a rapid enlargement, which is mostly transient, whereas axon shafts show a more delayed and progressive increase in diameter. Simulations of AP propagation incorporating these morphological dynamics predicted bidirectional effects on AP conduction speed. The predictions were confirmed by electrophysiological experiments, revealing a phase of slowed down AP conduction, which is linked to the transient enlargement of the synaptic boutons, followed by a sustained increase in conduction speed that accompanies the axon shaft widening induced by high-frequency AP firing. Taken together, our study outlines a morphological plasticity mechanism for dynamically fine-tuning AP conduction velocity, which potentially has wide implications for the temporal transfer of information in the brain.

Oligonucleotide synthesis catalyzed by the Zn/2+/ ion

NASA Technical Reports Server (NTRS)

Sawai, H.; Orgel, L. E.

1975-01-01

Results of experiments are reported in which Zn(2+) ion catalyzed the formation of oligonucleotides from nucleoside phosphorimidazolides in aqueous solution, even in the absence of a template. Specifically, the imidazolides (ImpU or ImpA) polymerized to form ImpApA, and pApA, pApApA, and pApApApA, or the analogous uracil compounds. In addition, the expected hydrolysis products of the hydrolysis of ImpA were formed (pA, imidazole). Judging from the ratio of pA(n) over pA (with and without zinc ion), this ion increased the efficiency of phosphodiester-bond formation by up to 10 times. Possible mechanisms for the reaction are tentatively proposed.

Oncology Advanced Practitioners Bring Advanced Community Oncology Care.

PubMed

Vogel, Wendy H

2016-01-01

Oncology care is becoming increasingly complex. The interprofessional team concept of care is necessary to meet projected oncology professional shortages, as well as to provide superior oncology care. The oncology advanced practitioner (AP) is a licensed health care professional who has completed advanced training in nursing or pharmacy or has completed training as a physician assistant. Oncology APs increase practice productivity and efficiency. Proven to be cost effective, APs may perform varied roles in an oncology practice. Integrating an AP into an oncology practice requires forethought given to the type of collaborative model desired, role expectations, scheduling, training, and mentoring.

Protection of Flos Lonicerae against acetaminophen-induced liver injury and its mechanism.

PubMed

Jiang, Ping; Sheng, Yu-chen; Chen, Yu-hao; Ji, Li-li; Wang, Zheng-tao

2014-11-01

This study aims to observe the protective action of Flos Lonicerae (FL) aqueous extract against acetaminophen (AP)-induced liver injury and its mechanism. Results show that FL decreases AP-increased serum alanine/aspartate transaminases (ALT/AST) activity, as well as total bilirubin (TB) amount, in mice. Histological evaluation of the liver further confirms the protection of FL against AP-induced hepatotoxicity. TdT-mediated biotin-dUTP nick-end labeling (TUNEL) assay shows that FL reduces AP-increased apoptotic cells. Furthermore, AP-decreased liver glutamate-cysteine ligase (GCL) enzymatic activity and glutathione (GSH) amount are both reversed by FL because of the increased expression of the catalytic subunit of GCL (GCLC) protein. The amount of chlorogenic acid (CGA), caffeic acid, and luteolin, the main active compounds in FL, is detected by high-performance liquid chromatography (HPLC). In addition, cell viability assay demonstrates that polyphenols in FL, such as CGA, caffeic acid, as well as isochlorogenic acids A, B, and C, can reverse AP-induced cytotoxicity. In conclusion, FL can prevent AP-induced liver injury by inhibiting apoptosis. The cellular antioxidant enzyme GCL is also involved in such protection. Polyphenols may be the main active hepato-protective ingredients in FL. Copyright © 2014 Elsevier B.V. All rights reserved.

The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications

PubMed Central

Dumnicka, Paulina; Maduzia, Dawid; Ceranowicz, Piotr; Olszanecki, Rafał; Drożdż, Ryszard; Kuśnierz-Cabala, Beata

2017-01-01

Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients. PMID:28208708

Heart Failure with Preserved Ejection Fraction: Comparison of Patients With and Without Angina Pectoris (From the Duke Databank for Cardiovascular Disease)

PubMed Central

Mentz, Robert J.; Broderick, Samuel; Shaw, Linda K.; Fiuzat, Mona; O'Connor, Christopher M.

2013-01-01

Objectives We aimed to investigate the characteristics and outcomes of patients with heart failure with preserved ejection fraction (HFpEF) and angina pectoris (AP). Background AP is a predictor of adverse events in patients with heart failure with reduced EF. The implications of AP in HFpEF are unknown. Methods We analyzed HFpEF patients (EF≥50%) who underwent coronary angiography at Duke University Medical Center from 2000–2010 with and without AP in the previous 6 weeks. Time to first event was examined using Kaplan-Meier methods for the primary endpoint of death/myocardial infarction (MI)/revascularization/stroke (i.e., MACE) and secondary endpoints of death/MI/revascularization, death/MI/stroke, death/MI, death and cardiovascular death/cardiovascular hospitalization. Results In the Duke Databank, 3517 patients met criteria for inclusion and 1402 (40%) had AP. Those with AP were older with more comorbidities, and prior revascularization vs. non-AP patients. AP patients more often received beta-blockers, ACE-inhibitors, nitrates, and statins (all P<0.05). In unadjusted analysis, AP patients had increased MACE and death/MI/revascularization (both P <0.001), lower rates of death and death/MI (both P<0.05), and similar rates of death/MI/stroke and cardiovascular death/cardiovascular hospitalization (both P>0.1). After multivariable adjustment, those with AP remained at increased risk for MACE (Hazard Ratio [HR] 1.30; 95% Confidence Interval [CI], 1.17–1.45) and death/MI/revascularization (HR 1.29; 95% CI, 1.15–1.43), but were at similar risk for other endpoints (P>0.06). Conclusions AP in HFpEF patients with a history of coronary artery disease is common despite medical therapy and is independently associated with increased MACE due to revascularization with similar risk of death, MI, and hospitalization. PMID:24161322

Di-Adenosine Tetraphosphate (Ap4A) Metabolism Impacts Biofilm Formation by Pseudomonas fluorescens via Modulation of c-di-GMP-Dependent Pathways▿

PubMed Central

Monds, Russell D.; Newell, Peter D.; Wagner, Jeffrey C.; Schwartzman, Julia A.; Lu, Wenyun; Rabinowitz, Joshua D.; O'Toole, George A.

2010-01-01

Dinucleoside tetraphosphates are common constituents of the cell and are thought to play diverse biological roles in organisms ranging from bacteria to humans. In this study we characterized two independent mechanisms by which di-adenosine tetraphosphate (Ap4A) metabolism impacts biofilm formation by Pseudomonas fluorescens. Null mutations in apaH, the gene encoding nucleoside tetraphosphate hydrolase, resulted in a marked increase in the cellular level of Ap4A. Concomitant with this increase, Pho regulon activation in low-inorganic-phosphate (Pi) conditions was severely compromised. As a consequence, an apaH mutant was not sensitive to Pho regulon-dependent inhibition of biofilm formation. In addition, we characterized a Pho-independent role for Ap4A metabolism in regulation of biofilm formation. In Pi-replete conditions Ap4A metabolism was found to impact expression and localization of LapA, the major adhesin regulating surface commitment by P. fluorescens. Increases in the level of c-di-GMP in the apaH mutant provided a likely explanation for increased localization of LapA to the outer membrane in response to elevated Ap4A concentrations. Increased levels of c-di-GMP in the apaH mutant were associated with increases in the level of GTP, suggesting that elevated levels of Ap4A may promote de novo purine biosynthesis. In support of this suggestion, supplementation with adenine could partially suppress the biofilm and c-di-GMP phenotypes of the apaH mutant. We hypothesize that changes in the substrate (GTP) concentration mediated by altered flux through nucleotide biosynthetic pathways may be a significant point of regulation for c-di-GMP biosynthesis and regulation of biofilm formation. PMID:20154123

Di-adenosine tetraphosphate (Ap4A) metabolism impacts biofilm formation by Pseudomonas fluorescens via modulation of c-di-GMP-dependent pathways.

PubMed

Monds, Russell D; Newell, Peter D; Wagner, Jeffrey C; Schwartzman, Julia A; Lu, Wenyun; Rabinowitz, Joshua D; O'Toole, George A

2010-06-01

Dinucleoside tetraphosphates are common constituents of the cell and are thought to play diverse biological roles in organisms ranging from bacteria to humans. In this study we characterized two independent mechanisms by which di-adenosine tetraphosphate (Ap4A) metabolism impacts biofilm formation by Pseudomonas fluorescens. Null mutations in apaH, the gene encoding nucleoside tetraphosphate hydrolase, resulted in a marked increase in the cellular level of Ap4A. Concomitant with this increase, Pho regulon activation in low-inorganic-phosphate (P(i)) conditions was severely compromised. As a consequence, an apaH mutant was not sensitive to Pho regulon-dependent inhibition of biofilm formation. In addition, we characterized a Pho-independent role for Ap4A metabolism in regulation of biofilm formation. In P(i)-replete conditions Ap4A metabolism was found to impact expression and localization of LapA, the major adhesin regulating surface commitment by P. fluorescens. Increases in the level of c-di-GMP in the apaH mutant provided a likely explanation for increased localization of LapA to the outer membrane in response to elevated Ap4A concentrations. Increased levels of c-di-GMP in the apaH mutant were associated with increases in the level of GTP, suggesting that elevated levels of Ap4A may promote de novo purine biosynthesis. In support of this suggestion, supplementation with adenine could partially suppress the biofilm and c-di-GMP phenotypes of the apaH mutant. We hypothesize that changes in the substrate (GTP) concentration mediated by altered flux through nucleotide biosynthetic pathways may be a significant point of regulation for c-di-GMP biosynthesis and regulation of biofilm formation.

Nuclear envelope breakdown and mitosis in sand dollar embryos is inhibited by microinjection of calcium buffers in a calcium-reversible fashion, and by antagonists of intracellular Ca2+ channels.

PubMed

Silver, R B

1989-01-01

Transient elevations in intracellular free Ca2+ are believed to signal the initiation of mitosis. This model predicts that mitosis might be arrested prior to nuclear envelope breakdown (NEB) or anaphase onset if intracellular Ca2+ concentration is buffered or dampened. Microinjection of a discrete dose of Ca2+ into the cell might then release the cell to resume mitotic cycling. Experimentally, one blastomere of two cell sand dollar (Echinaracnius parma) embryos was microinjected with Ca2+ buffers, Ca2+ solutions, or Ca2+ channel antagonists; the uninjected blastomere was the control. Cells were loaded with 10 pl doses of the Ca2+ buffer antipyrylazo III (ApIII) at specific times in the cell cycle to attempt a competitive inhibition of Ca2+-dependent steps in NEB and initiation of mitosis. Injection of 50 microM ApIII 6 min prior to NEB blocked NEB and further cell cycling. Injections of solutions between 0 and 30 microM ApIII were without observable effect. Control injections had no observable effect on the injected cell. Cells injected with 50 microM ApIII 2 min prior to the onset of anaphase in control cells were blocked in metaphase. Cells were sensitive to Ca2+ buffer injections 6 min prior to NEB (with a 40- to 45-sec duration), and 2 min prior to anaphase onset (with a 10- to 20-sec duration). Vital staining of these cells with H33342 demonstrated that they contained only one nucleus that had the same fluorescence intensity as seen prior to microinjection, and thus did not undergo DNA synthesis following the imposition of the Ca2+ buffer block to mitosis. Cells arrested in this fashion did not spontaneously resume mitotic cycling. This Ca2+ buffer-induced mitotic arrest was, however, experimentally reversible. Cells arrested with 50 microM ApIII 6 min prior to NEB could be returned to mitotic activity by injecting 300 microM CaCl2 5 min after the ApIII injection. The double injected cells resumed cycling, NEB, and mitosis after a delay of one cell cycle period, and remained one cell cycle out of phase with the sister (control) cell. Microinjection of antagonists of endomembrane Ca2+ channels inhibited NEB and anaphase onset in a concentration- and time-dependent fashion. The effective doses of compounds tested were 7 micrograms/ml ryanodine and 500 micrograms/ml TMB-8. These results indicate that a transient elevation of intracellular Ca2+ from endomembrane stores is required to initiate mitotic events, namely NEB and anaphase onset.(ABSTRACT TRUNCATED AT 400 WORDS)

Mechanism of aminopyridine-induced release of [3H]dopamine from rat brain synaptosomes.

PubMed

Scheer, H W; Lavoie, P A

1991-01-01

1. Aminopyridines (APs) induced the release of [3H]dopamine (3H-DA) from rat synaptosomal preparations. 2. 4-AP and 3,4-DAP were of equal efficacy in inducing release of 3H-DA; 3-AP, 2-AP and 2,6-AP were less active; pyridine and pyridine-4-carboxylamide were inactive. 3. Cd2+ was more effective in inhibiting 4-AP-induced release of 3H-DA (IC50 approximately 4 microM) than Co2+ and Ni2+ (IC50s approximately 500 microM). 4. While 4-AP increased the 45Ca2+ content of whole synaptosomal preparations, no effect of 4-AP on 45Ca2+ content was observed in lysed synaptosomal preparations. 5. 4-AP-induced 45Ca2+ uptake was inhibited by Cd2+, Ni2+ and Co2+ in concentration ranges similar to those inhibiting 3H-DA release.

Influence of atmospheric pressure on the incidence of spontaneous pneumothorax.

PubMed

Díaz, Raúl; Díez, Manuel Mariano; Medrano, María José; Vera, Cristina; Guillamot, Paloma; Sánchez, Ana; Ratia, Tomás; Granell, Javier

2014-01-01

This study analyses the relationship between the incidence of idiopathic spontaneous pneumothorax (ISP) and atmospheric pressure (AP). A total of 288 cases of ISP were included, 229 men and 59 women. The AP of the day of diagnosis, of the 3 prior days and the monthly average was registered. The association between the incidence of ISP and AP was analyzed by calculating standardized incidence ratio (SIR) and Poisson regression. The AP on the day of admission (mean±standard deviation) (1,017.9±7 hectopascals [hPa]) was higher than the monthly average AP (1,016.9±4.1 hPa) (P=.005). There was a monthly distribution pattern of ISP with the highest incidence in the months of January, February and September and the lowest in April. When AP was less than 1,014 hPa, there were fewer cases registered than what would statistically have been expected (58/72 cases). In contrast, when the pressure was higher than 1,019 hPa, the registered cases were more than expected (109/82 cases) (SIR=1.25; 95% CI: 1.04 to 1.51). The risk of ISP increased 1.15 times (95% CI: 1.05 to 1.25, P=.001) for each hPa of AP, regardless of sex, age and monthly average AP. A dose-response relationship was observed, with progressive increases in risk (IRR=1.06 when the AP was 1,014-1016 hPa; 1.17 hPa when the AP was 1,016-1,019 hPa and 1.69 when AP was superior to 1,019 hPa) (P for trend=.089). The AP is a risk factor for the onset of idiopathic spontaneous pneumothorax. Copyright © 2012 AEC. Published by Elsevier Espana. All rights reserved.

AP-1 Oligodeoxynucleotides Reduce Aortic Elastolysis in a Murine Model of Marfan Syndrome.

PubMed

Arif, Rawa; Zaradzki, Marcin; Remes, Anca; Seppelt, Philipp; Kunze, Reiner; Schröder, Hannes; Schwill, Simon; Ensminger, Stephan M; Robinson, Peter N; Karck, Matthias; Müller, Oliver J; Hecker, Markus; Wagner, Andreas H; Kallenbach, Klaus

2017-12-15

Marfan syndrome is characterized by high expression of matrix metalloproteinases (MMPs) in aortic smooth muscle cells (AoSMCs) associated with medial elastolysis and aortic root aneurysm. We aimed to reduce aortic elastolysis through decrease of MMP expression with decoy oligodeoxynucleotides (dODNs) neutralizing the transcription factor activating factor-1 (AP-1). AP-1 abundance in nuclear extracts as well as MMP-2 and MMP-9 expression were significantly increased in isolated mAoSMC of mgR/mgR Marfan mice compared to wild-type cells. Exposure to AP-1 neutralizing dODNs resulted in a significant reduction of basal and interleukin-1β-stimulated MMP expression and activity in mAoSMCs. Moreover, increased migration and formation of superoxide radical anions was substantially decreased in mAoSMCs by AP-1 dODN treatment. Aortic grafts from donor Marfan mice were treated with AP-1- dODN ex vivo and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Pretreatment of aortic grafts with AP-1 dODN led to reduced elastolysis, macrophage infiltration, and MMP activity. Permeability of the endothelial monolayer was increased for dODN in mgR/mgR aortae with observed loss of tight junction proteins ZO-1 and occludin, enabling dODN to reach the tunica media. Targeting AP-1 activity offers a new potential strategy to treat the vascular phenotype associated with Marfan syndrome. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Uncoupling Lipid Metabolism from Inflammation through Fatty Acid Binding Protein-Dependent Expression of UCP2

PubMed Central

Xu, Hongliang; Hertzel, Ann V.; Steen, Kaylee A.; Wang, Qigui; Suttles, Jill

2015-01-01

Chronic inflammation in obese adipose tissue is linked to endoplasmic reticulum (ER) stress and systemic insulin resistance. Targeted deletion of the murine fatty acid binding protein (FABP4/aP2) uncouples obesity from inflammation although the mechanism underlying this finding has remained enigmatic. Here, we show that inhibition or deletion of FABP4/aP2 in macrophages results in increased intracellular free fatty acids (FFAs) and elevated expression of uncoupling protein 2 (UCP2) without concomitant increases in UCP1 or UCP3. Silencing of UCP2 mRNA in FABP4/aP2-deficient macrophages negated the protective effect of FABP loss and increased ER stress in response to palmitate or lipopolysaccharide (LPS). Pharmacologic inhibition of FABP4/aP2 with the FABP inhibitor HTS01037 also upregulated UCP2 and reduced expression of BiP, CHOP, and XBP-1s. Expression of native FABP4/aP2 (but not the non-fatty acid binding mutant R126Q) into FABP4/aP2 null cells reduced UCP2 expression, suggesting that the FABP-FFA equilibrium controls UCP2 expression. FABP4/aP2-deficient macrophages are resistant to LPS-induced mitochondrial dysfunction and exhibit decreased mitochondrial protein carbonylation and UCP2-dependent reduction in intracellular reactive oxygen species. These data demonstrate that FABP4/aP2 directly regulates intracellular FFA levels and indirectly controls macrophage inflammation and ER stress by regulating the expression of UCP2. PMID:25582199

Severe hypertriglyceridemia and factors associated with acute pancreatitis in an integrated health care system.

PubMed

Rashid, Nazia; Sharma, Puza P; Scott, Ronald D; Lin, Kathy J; Toth, Peter P

2016-01-01

To evaluate patient characteristics, treatment patterns, comorbidities, and risk factors associated with the development of acute pancreatitis (AP) in patients with severe hypertriglyceridemia (HTG) in an integrated health care delivery system. We identified a retrospective cohort of severe HTG patients with a fasting triglyceride level ≥ 1000 mg/dL during January 1, 2007 to June 30, 2013 (index date) in an integrated health care delivery system. Patients were aged ≥18 years on index date and had 12 months of continuous membership and drug eligibility before the index date and during postindex including index date. Baseline patient characteristics, comorbidities, and risk factors were evaluated during 12-month preindex. Outcomes such as development of AP, treatment patterns, adherence to index therapy, and change in triglyceride (TG) laboratory levels were evaluated during postindex. Descriptive statistics were used to identify differences between patients developing AP vs no development of AP. A stepwise multivariate logistic regression and backward elimination method were used to assess statistically significant predictive factors associated with development of AP vs no AP. We identified 5550 patients with severe HTG, and 5.4% of these patients developed AP during postindex. Patients were mostly male (≥70%) in both groups; however, younger in the AP group (45 years ± 10.6) vs no AP group (50 years ± 11.4) with P value < .0001. The AP group had higher baseline Charslon Comorbidity Index score, alcohol abuse history (42.2%), any pancreatitis history (51.5%), diabetes (47%), and hypertension (55%), vs the no AP group (P values < .05). Patients in the AP group had higher baseline mean TG levels (2148, SD ± 1578) vs the no AP group (1559, SD ± 861), P value < .0001. Over 50% of the patients were prescribed their index therapy by a primary care provider. Predictive factors associated with the development of AP included younger age, alcohol use, and prior history of any pancreatitis, hypertension, renal disease stage 4, and other prescriber specialty. From parameters estimates, for each 100 mg/dL unit of increase in the TG level above 1000 mg/dL, there was a 3 percent increase in risk of developing AP. Patients with severe HTG are at a higher risk of developing AP. A number of comorbidities, risk factors, and baseline TG levels are associated with an increased incidence of AP. Patients with severe HTG are underdiagnosed, undertreated and are nonadherent to their index lipid therapy. There is a need to better define optimal approaches to treating severe HTG so as to reduce the incidence of AP. Economic studies are also needed to evaluate the burden of AP on various health care systems. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial

PubMed Central

2012-01-01

Introduction To evaluate whether alkaline phosphatase (AP) treatment improves renal function in sepsis-induced acute kidney injury (AKI), a prospective, double-blind, randomized, placebo-controlled study in critically ill patients with severe sepsis or septic shock with evidence of AKI was performed. Methods Thirty-six adult patients with severe sepsis or septic shock according to Systemic Inflammatory Response Syndrome criteria and renal injury defined according to the AKI Network criteria were included. Dialysis intervention was standardized according to Acute Dialysis Quality Initiative consensus. Intravenous infusion of alkaline phosphatase (bolus injection of 67.5 U/kg body weight followed by continuous infusion of 132.5 U/kg/24 h for 48 hours, or placebo) starting within 48 hours of AKI onset and followed up to 28 days post-treatment. The primary outcome variable was progress in renal function variables (endogenous creatinine clearance, requirement and duration of renal replacement therapy, RRT) after 28 days. The secondary outcome variables included changes in circulating inflammatory mediators, urinary excretion of biomarkers of tubular injury, and safety. Results There was a significant (P = 0.02) difference in favor of AP treatment relative to controls for the primary outcome variable. Individual renal parameters showed that endogenous creatinine clearance (baseline to Day 28) was significantly higher in the treated group relative to placebo (from 50 ± 27 to 108 ± 73 mL/minute (mean ± SEM) for the AP group; and from 40 ± 37 to 65 ± 30 mL/minute for placebo; P = 0.01). Reductions in RRT requirement and duration did not reach significance. The results in renal parameters were supported by significantly more pronounced reductions in the systemic markers C-reactive protein, Interleukin-6, LPS-binding protein and in the urinary excretion of Kidney Injury Molecule-1 and Interleukin-18 in AP-treated patients relative to placebo. The Drug Safety Monitoring Board did not raise any issues throughout the trial. Conclusions The improvements in renal function suggest alkaline phosphatase is a promising new treatment for patients with severe sepsis or septic shock with AKI. Trial Registration www.clinicaltrials.gov: NCTNCT00511186 PMID:22269279

AP1 binding site is another target of FGF2 regulation of bone sialoprotein gene transcription.

PubMed

Takai, Hideki; Araki, Shouta; Mezawa, Masaru; Kim, Dong-Soon; Li, Xinyue; Yang, Li; Li, Zhengyang; Wang, Zhitao; Nakayama, Youhei; Ogata, Yorimasa

2008-02-29

Bone sialoprotein (BSP) is an early marker of osteoblast differentiation. We previously reported that fibroblast growth factor 2 (FGF2) regulates BSP gene transcription via FGF2 response element (FRE) in the proximal promoter of rat BSP gene. We here report that activator protein 1 (AP1) binding site overlapping with glucocorticoid response element (GRE) AP1/GRE in the rat BSP gene promoter is another target of FGF2. Using the osteoblastic cell line ROS17/2.8, we determined that BSP mRNA levels increased by 10 ng/ml FGF2 at 6 and 12 h. Runx2 protein levels increased by FGF2 (10 ng/ml) at 3 h. Treatment of ROS17/2.8 cells with FGF2 (10 ng/ml, 12 h) increased luciferase activities of constructs including -116 to +60 and -938 to +60 of the rat BSP gene promoter. Effects of FGF2 abrogated in constructs included 2 bp mutations in the FRE and AP1/GRE elements. Luciferase activities induced by FGF2 were blocked by tyrosine kinase inhibitor herbimycin A, src-tyrosine kinase inhibitor PP1 and MAP kinase kinase inhibitor U0126. Gel shift analyses showed that FGF2 increased binding of FRE and AP1/GRE elements. Notably, the AP1/GRE-protein complexes were supershifted by Smad1 and c-Fos antibodies, c-Jun and Dlx5 antibodies disrupted the complexes formation, on the other hand AP1/GRE-protein complexes did not change by Runx2 antibody. These studies demonstrate that FGF2 stimulates BSP gene transcription by targeting the FRE and AP1/GRE elements in the rat BSP gene promoter.

Responses of alkaline phosphatase activity to phosphorus stress in Daphnia magna.

PubMed

McCarthy, S D S; Rafferty, S P; Frost, P C

2010-01-15

We examined how alkaline phosphatase (AP) activity within the bodies and in the materials released by the crustacean Daphnia magna responds to variable algal food phosphorus (P)-content. We found that Daphnia eating P-poor food (C:P approximately 700) had significantly higher AP activity in their bodies on a mass-specific basis compared with individuals eating P-rich food (C:P approximately 100). This dietary P effect on AP activity was not altered by Daphnia starvation but was partially related to differences in the P concentration of animal body homogenates. By contrast, poor P-nutrition of Daphnia lowered AP activity in released materials compared with that measured from their P-sufficient conspecifics. Moreover, AP activity in Daphnia release was lowest in animals consuming P-poor food for longer time periods. Our results support the hypothesis that AP activity increases inside P-limited Daphnia as a mechanism to increase P-acquisition and retention from ingested algae in these nutritionally stressed animals. The lower level of AP activity present in the water of P-deprived animals could reflect a change from largely free to membrane-bound AP isotypes in the digestive tracts of P-starved animals or a decrease in the shedding of membrane-anchored AP from their intestinal lining. These results supplement accumulating evidence that P-poor algal food reduces the dietary mineral P available to Daphnia. In addition, animal body AP activity measurements, with some refinement, may prove useful as an in situ indicator of P-stress in aquatic consumers.

High concentrations of intracellular Ap4A and/or Ap5A in developing Myxococcus xanthus cells inhibit sporulation.

PubMed

Kimura, Yoshio; Tanaka, Chihiro; Sasaki, Katsuho; Sasaki, Masashi

2017-01-01

Diadenosine polyphosphates (ApnA) are thought to act as signalling molecules regulating stress responses and biofilm formation in prokaryotes. However, ApnA function in Myxococcus xanthus remains unknown. Here, we investigated the role of ApnA in M. xanthus, using the wild-type and ApnA hydrolase (apaH) mutant strains exposed to various stress conditions. In both wild-type and apaH mutant cells cultured on starvation medium (CF agar), the levels of intracellular diadenosine tetraphosphate (Ap4A) and pentaphosphate (Ap5A) increased several fold during the first 16 h of development and decreased gradually thereafter. The levels of Ap4A and Ap5A in the apaH mutant were about 5- and 11-fold higher than those in the wild-type strain at 16 h, respectively. ApnA hydrolase activity of the wild-type strain increased 1.5-fold during the first 8 h of development, and it then gradually decreased. The apaH mutant formed spores 1-2 days after the wild-type strain did, and the yield of viable spores was 5.5 % of that in the wild-type strain 5 days after inoculation onto CF agar. These results suggest the possibility that high intracellular levels of Ap4A and/or Ap5A may inhibit M. xanthus sporulation at the early stage of development and that the bacteria reduce intracellular Ap4A and Ap5A accumulation through ApnA hydrolase activity.

The soil sulphate effect and maize plant (Zea mays L.) growth of sulphate reducing bacteria (SRB) inoculation in acid sulfate soils with the different soil water condition

NASA Astrophysics Data System (ADS)

Asmarlaili, S.; Rauf, A.; Hanafiah, D. S.; Sudarno, Y.; Abdi, P.

2018-02-01

The objective of the study was to determine the potential application of sulphate reducing bacteria on acid sulfate soil with different water content in the green house. The research was carried out in the Laboratory and Green House, Faculty of Agriculture, Universitas Sumatera Utara. This research used Randomized Block Design with two treatments factors, ie sulphate reducing bacteria (SRB) isolate (control, LK4, LK6, TSM4, TSM3, AP4, AP3, LK4 + TSM3, LK4 + AP4, LK4 + AP3, LK6 + TSM3, LK6 + AP4, LK6 + AP3, TSM4 + TSM3, TSM4 + AP4, TSM4 + AP3) and water condition (100% field capacity and 110% field capacity). The results showed that application of isolate LK4 + AP4 with water condition 110% field capacity decreased the soil sulphate content (27.38 ppm) significantly after 6 weeks. Application of isolate LK4 + AP3 with water condition 110% field capacity increased soil pH (5.58) after-week efficacy 6. Application of isolate LK4 with water condition 110% field capacity increased plant growth (140 cm; 25.74 g) significantly after week 6. The best treatment was application isolate LK4 with water condition 110% field Capacity (SRB population 2.5x108; soil sulphate content 29.10ppm; soil acidity 4.78; plant height 140cm; plant weight 25.74g).

The effects of roflumilast on the pancreas and remote organs in a cerulein-induced experimental acute pancreatitis model in rats.

PubMed

Uslukaya, Omer; Turkoglu, Ahmet; Yazgan, Umit Can; Kaplan, Ibrahim; Ibiloglu, Ibrahim; Kapan, Murat; Gumus, Metehan

2016-12-01

Systemic damage in acute pancreatitis (AP) can be characterized by oxidative stress and the release of pro-inflammatory cytokines. Roflumilast has been shown to be a potent anti-inflammatory and antioxidant agent. In the present study, we aimed to investigate the effect of roflumilast in cerulein-induced AP. Thirty-two male rats were divided into four groups: group 1 (sham), group 2 (Roflumilast), group 3 (AP), and group 4 (AP + Roflumilast). AP was induced by injecting 4 × 75 μg/kg of body weight at an interval of 1 h. Rats were killed after 12 h following the last cerulein administration. AP was confirmed by measuring the serum amylase level and inflammatory features. Morphological changes were observed in the pancreas. Amylase levels were higher in the AP and AP + Roflumilast groups than the sham and Roflumilast groups. The serum levels of TNF-α, IL-1β, and IL-6 increased in the AP group, whereas they decreased in the Roflumilast group. The total oxidant activity (TOA) was higher and the total antioxidant capacity (TAC) was lower in the AP group. The administration of roflumilast decreased the TOA and increased the TAC in comparison with the AP group (p < 0.05 for both). Roflumilast significantly decreases oxidative stress and inflammatory mediators in the plasma, pancreas, and lung in cerulein-induced AP rats.

Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle

PubMed Central

Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R.

2013-01-01

Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses. PMID:23657274

Adaptor protein complexes-1 and 3 are involved at distinct stages of flavivirus life-cycle.

PubMed

Agrawal, Tanvi; Schu, Peter; Medigeshi, Guruprasad R

2013-01-01

Intracellular protein trafficking pathways are hijacked by viruses at various stages of viral life-cycle. Heterotetrameric adaptor protein complexes (APs) mediate vesicular trafficking at distinct intracellular sites and are essential for maintaining the organellar homeostasis. In the present study, we studied the effect of AP-1 and AP-3 deficiency on flavivirus infection in cells functionally lacking these proteins. We show that AP-1 and AP-3 participate in flavivirus life-cycle at distinct stages. AP-3-deficient cells showed delay in initiation of Japanese encephalitis virus and dengue virus RNA replication, which resulted in reduction of infectious virus production. AP-3 was found to colocalize with RNA replication compartments in infected wild-type cells. AP-1 deficiency affected later stages of dengue virus infection where increased intracellular accumulation of infectious virus was observed. Therefore, our results propose a novel role for AP-1 and AP-3 at distinct stages of infection of some of the RNA viruses.

Femoral sizing in total knee arthroplasty is rotation dependant.

PubMed

Koninckx, Angelique; Deltour, Arnaud; Thienpont, Emmanuel

2014-12-01

The mismatch between the medio-lateral (ML) and the antero-posterior (AP) size of femoral components in total knee arthroplasty (TKA) has been linked to gender, ethnicity, morphotype and height differences in patients. The hypothesis of this study was that the AP size measurement of a femoral component increases with more external rotation in posterior referencing TKA. During a 2-year period, 201 patients were included in this prospective study. The AP distance of the distal femur was measured with an AP sizer of the Vanguard (Biomet, Warsaw, US) knee system. This AP sizer allows to dial in external rotation by 1° increments and to determine the femoral size with an anterior boom. AP size was noted at 0°, 3° and 5° of external rotation and then compared for ML matching. Antero-posterior and corresponding ML sizes match perfectly for the Vanguard at 0° of external rotation and a central boom position on the anterior femoral surface. Then, the anterior boom was positioned on the antero-lateral cortex and the AP size increased a mean (SD) 1 (0.5) mm. With 3° of external rotation, the AP size increased a mean (SD) 2.3 (0.4) mm and for 5° a mean (SD) 3.8 (0.3) mm (P < 0.05). This increase in AP size resulted in ML overhang of 2.2 (1.2) mm for 3° and 4.8 (2.6) mm for 5° (P < 0.05). Antero-posterior size measurement of the distal femur is determined by the anatomy of the anterior surface with a higher antero-lateral cortex and the amount of external rotation that is dialled in during surgery. Since these parameters vary case per case, the availability of narrow components offers more surgical options to the surgeon and its importance extends beyond the gender aspect allowing different amounts of external rotation to be used without ML overhang. II.

Risk Factors for Pancreatitis in Older Women: The Iowa Women’s Health Study

PubMed Central

Prizment, Anna E.; Jensen, Eric H.; Hopper, Anne M; Virnig, Beth A.; Anderson, Kristin E.

2015-01-01

Purpose Pancreatitis – an inflammation of pancreas – is a severe and costly disease. While many risk factors for pancreatitis are known, many cases, especially in elderly, are of unknown etiology. Methods Risk factors for acute (AP) and chronic pancreatitis (CP) were assessed in a prospective cohort (n=36,436 women, aged ≥65 years). Exposures were self-reported at baseline. Pancreatitis was ascertained by linkage to Medicare claims (1986–2004) categorized by a physician as: “AP”, 1 AP episode (n=511); or “CP”, 2+ AP or 1+ CP episodes (n=149). Results Multivariable odds ratios (OR) and 95% CI for AP and CP were calculated using multinomial logistic regression. Alcohol use was not associated with AP or CP. Heavy smoking (40+ versus 0 pack-years) was associated with a 2-fold increased OR for CP. For BMI ≥30 versus <25 kg/m2, the ORs were 1.35 (1.07–1.70) for AP (p-trend=0.009) and 0.59 (0.37–0.94) for CP (p-trend=0.01). ORs for AP and CP were increased for HRT use, heart disease, and hypertension. There were positive significant associations between protein and total fat intake for CP and AP. Conclusions We identified factors associated with AP and CP that may be specific to older women. PMID:25656921

Ap4A induces apoptosis in human cultured cells.

PubMed

Vartanian, A; Alexandrov, I; Prudowski, I; McLennan, A; Kisselev, L

1999-07-30

Diadenosine oligophosphates (Ap(n)A) have been proposed as intracellular and extracellular signaling molecules in animal cells. The ratio of diadenosine 5',5'''-P1,P3-triphosphate to diadenosine 5',5'''-P1,P4-tetraphosphate (Ap3A/Ap4A) is sensitive to the cellular status and alters when cultured cells undergo differentiation or are treated with interferons. In cells undergoing apoptosis induced by DNA topoisomerase II inhibitor VP16, the concentration of Ap3A decreases significantly while that of Ap4A increases. Here, we have examined the effects of exogenously added Ap3A and Ap4A on apoptosis and morphological differentiation. Penetration of Ap(n)A into cells was achieved by cold shock. Ap4A at 10 microM induced programmed cell death in human HL60, U937 and Jurkat cells and mouse VMRO cells and this effect appeared to require Ap4A breakdown as hydrolysis-resistant analogues of Ap4A were inactive. On its own, Ap3A induced neither apoptosis nor cell differentiation but did display strong synergism with the protein kinase C activators 12-deoxyphorbol-13-O-phenylacetate and 12-deoxyphorbol-13-O-phenylacetate-20-acetate in inducing differentiation of HL60 cells. We propose that Ap4A and Ap3A are physiological antagonists in determination of the cellular status: Ap4A induces apoptosis whereas Ap3A is a co-inductor of differentiation. In both cases, the mechanism of signal transduction remains unknown.

Corpus callosum volumes in the 5 years following the first-episode of schizophrenia: Effects of antipsychotics, chronicity and maturation.

PubMed

de Moura, Mariana T M; Zanetti, Marcus V; Duran, Fabio L S; Schaufelberger, Maristela S; Menezes, Paulo R; Scazufca, Marcia; Busatto, Geraldo F; Serpa, Mauricio H

2018-01-01

White matter (WM) structural changes, particularly affecting the corpus callosum (CC), seem to be critically implicated in psychosis. Whether such abnormalities are progressive or static is still a matter of debate in schizophrenia research. Aberrant maturation processes might also influence the longitudinal trajectory of age-related CC changes in schizophrenia patients. We investigated whether patients with first-episode schizophrenia-related psychoses (FESZ) would present longitudinal CC and whole WM volume changes over the 5 years after disease onset. Thirty-two FESZ patients and 34 controls recruited using a population-based design completed a 5-year assessment protocol, including structural MRI scanning at baseline and follow-up. The linear effects of disease duration, clinical outcome and antipsychotic (AP) use over time on WM and CC volumes were studied using both voxelwise and volume-based morphometry analyses. We also examined maturation/aging abnormalities through cross-sectional analyses of age-related trajectories of total WM and CC volume changes. No interaction between diagnosis and time was observed, and clinical outcome did not influence CC volumes in patients. On the other hand, FESZ patients continuously exposed to AP medication showed volume increase over time in posterior CC. Curve-estimation analyses revealed a different aging pattern in FESZ patients versus controls: while patients displayed a linear decline of total WM and anterior CC volumes with age, a non-linear trajectory of total WM and relative preservation of CC volumes were observed in controls. Continuous AP exposure can influence CC morphology during the first years after schizophrenia onset. Schizophrenia is associated with an abnormal pattern of total WM and anterior CC aging during non-elderly adulthood, and this adds complexity to the discussion on the static or progressive nature of structural abnormalities in psychosis.

The effect of the stability threshold on time to stabilization and its reliability following a single leg drop jump landing.

PubMed

Fransz, Duncan P; Huurnink, Arnold; de Boode, Vosse A; Kingma, Idsart; van Dieën, Jaap H

2016-02-08

We aimed to provide insight in how threshold selection affects time to stabilization (TTS) and its reliability to support selection of methods to determine TTS. Eighty-two elite youth soccer players performed six single leg drop jump landings. The TTS was calculated based on four processed signals: raw ground reaction force (GRF) signal (RAW), moving root mean square window (RMS), sequential average (SA) or unbounded third order polynomial fit (TOP). For each trial and processing method a wide range of thresholds was applied. Per threshold, reliability of the TTS was assessed through intra-class correlation coefficients (ICC) for the vertical (V), anteroposterior (AP) and mediolateral (ML) direction of force. Low thresholds resulted in a sharp increase of TTS values and in the percentage of trials in which TTS exceeded trial duration. The TTS and ICC were essentially similar for RAW and RMS in all directions; ICC's were mostly 'insufficient' (<0.4) to 'fair' (0.4-0.6) for the entire range of thresholds. The SA signals resulted in the most stable ICC values across thresholds, being 'substantial' (>0.8) for V, and 'moderate' (0.6-0.8) for AP and ML. The ICC's for TOP were 'substantial' for V, 'moderate' for AP, and 'fair' for ML. The present findings did not reveal an optimal threshold to assess TTS in elite youth soccer players following a single leg drop jump landing. Irrespective of threshold selection, the SA and TOP methods yielded sufficiently reliable TTS values, while for RAW and RMS the reliability was insufficient to differentiate between players. Copyright © 2016 Elsevier Ltd. All rights reserved.

Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

PubMed

Passini, Elisa; Britton, Oliver J; Lu, Hua Rong; Rohrbacher, Jutta; Hermans, An N; Gallacher, David J; Greig, Robert J H; Bueno-Orovio, Alfonso; Rodriguez, Blanca

2017-01-01

Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC 50 /Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca 2+ -transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca 2+ /late Na + currents and Na + /Ca 2+ -exchanger, reduced Na + /K + -pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density (fast/late Na + and Ca 2+ currents) exhibit high susceptibility to depolarization abnormalities. Repolarization abnormalities in silico predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: in silico AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca 2+ -transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human in silico drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.

The Utility of the Systemic Inflammatory Respsonse Syndrome Score on Admission in Children With Acute Pancreatitis.

PubMed

Grover, Amit S; Kadiyala, Vivek; Banks, Peter A; Grand, Richard J; Conwell, Darwin L; Lightdale, Jenifer R

2017-01-01

Pediatric patients with acute pancreatitis (AP) may meet criteria at admission for the systemic inflammatory response syndrome (SIRS). Early SIRS in adults with AP is associated with severe disease. Our aim was to evaluate the importance of SIRS in children presenting with AP on various outcomes. This is a retrospective cohort study of children hospitalized with AP at Boston Children's Hospital in 2010. Increased length of stay (LOS) and/or admission to the intensive care unit (ICU) served as the primary outcomes. Statistical analyses of measures studied included the presence of SIRS, demographic, and clinical information present on admission. Fifty encounters, in which AP was the primary admitting diagnosis, were documented. Patients had a median LOS of 4.5 (interquartile range, 2-9) days. Systemic inflammatory response syndrome was present in 22 (44%) of 50 patients at admission. Systemic inflammatory response syndrome at admission was an independent predictor of increased LOS (odds ratio, 7.99; P = 0.045) as well as admission to the ICU (odds ratio, 12.06; P = 0.027). The presence of SIRS criteria on admission serves as a useful and easy-to-calculate predictor of increased LOS and admission to ICU in children with AP.

Activation of activator protein 2 alpha by aspirin alleviates atherosclerotic plaque growth and instability in vivo

PubMed Central

Yang, Jing-Jing; Li, Peng; Wang, Fu; Liang, Wen-Jing; Ma, Hui; Chen, Yuan; Ma, Zhi-Min; Li, Quan-Zhong; Peng, Qi-Sheng; Zhang, Yun; Wang, Shuang-Xi

2016-01-01

Aims Aspirin has been used for the secondary prevention and treatment of cardiovascular disease for several decades. We investigated the roles of transcriptional factor activator protein 2α (AP-2α) in the beneficial effects of aspirin in the growth and vulnerability of atherosclerotic plaque. Methods and Results In mice deficient of apolipoprotein E (Apoe-/-), aspirin (20, 50 mg/kg/day) suppressed the progression of atherosclerosis in aortic roots and increased the plaque stability in carotid atherosclerotic plaques induced by collar-placement. In vivo lentivirus-mediated RNA interference of AP-2α reversed the inhibitory effects of aspirin on atherosclerosis in Apoe-/- mice. Mechanically, aspirin increased AP-2α phosphorylation and its activity, upregulated IkBα mRNA and protein levels, and reduced oxidative stress in cultured vascular smooth muscle cells. Furthermore, deficiency of AP-2α completely abolished aspirin-induced upregulation of IkBα levels and inhibition of oxidative stress in Apoe-/- mice. Clinically, conventional doses of aspirin increased AP-2α phosphorylation and IkBα protein expression in humans subjects. Conclusion Aspirin activates AP-2α to upregulate IkBα gene expression, resulting in attenuations of plaque development and instability in atherosclerosis. PMID:27391154

Laser drive development for the APS Dynamic Compression Sector

NASA Astrophysics Data System (ADS)

Lagrange, Thomas; Swift, Damian; Reed, Bryan; Bernier, Joel; Kumar, Mukul; Hawreliak, James; Eggert, Jon; Dixit, Sham; Collins, Gilbert

2013-06-01

The Dynamic Compression Sector (DCS) at the APS synchrotron offers unprecedented possibilities for x-ray diffraction and scattering measurements in-situ during dynamic loading, including single-shot data collection with x-ray energies high enough (tens of kV) to study high-Z samples in transmission as well as reflection. Dynamic loading induced by laser ablation is an important component of load generation, as the duration, strain rate, and pressure can be controlled via the energy, spot size, and pulse shape. Using radiation hydrodynamics simulations, validated by experiments at several laser facilities, we have investigated the relationship between irradiance history and pressure for ablative loads designed to induce shock and ramp loading in the nanosecond to microsecond range, and including free ablation and also ablation confined by a transparent substrate. We have investigated the effects of lateral release, which constrains the minimum diameter of the focal spot for a given drive duration. In this way, we are able to relate the desired drive conditions to the total laser energy needed, which dictates the laser technologies suitable for a given type of experiment. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

Systematic review of hypertriglyceridemia-induced acute pancreatitis: A more virulent etiology?

PubMed

Carr, Rosalie A; Rejowski, Benjamin J; Cote, Gregory A; Pitt, Henry A; Zyromski, Nicholas J

2016-01-01

We sought to define the severity and natural history of hypertriglyceridemia induced acute pancreatitis (HTG-AP), specifically whether HTG-AP causes more severe AP than that caused by other etiologies. Systematic review of the English literature. Thirty-four studies (15 countries; 1972-2015) included 1340 HTG-AP patients (weighted mean prevalence of 9%). The median admission triglyceride concentration was 2622 mg/dl (range 1160-9769). Patients with HTG have a 14% weighted mean prevalence of AP. Plasmapheresis decreased circulating triglycerides, but did not conclusively affect AP mortality. Only 7 reports (n = 392 patients) compared severity of HTG-AP to that of AP from other etiologies. Of these, 2 studies found no difference in severity, while 5 suggested that HTG-AP patients may have increased severity compared to AP of other etiology. 1) hypertriglyceridemia is a relatively uncommon (9%) cause of acute pancreatitis; however, patients with hypertriglyceridemia have a high (14%) incidence of acute pancreatitis; 2) plasmapheresis may offer specific therapy unique to this patient population; and 3) data specifically comparing the severity of HTG-AP with AP caused by other etiologies are heterogeneous and scarce. Copyright © 2016. Published by Elsevier B.V.

78 FR 21817 - Amendment of Restricted Area R-6601; Fort A.P. Hill, VA

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-12

...; Airspace Docket No. 12-AEA-7] RIN 2120-AA66 Amendment of Restricted Area R-6601; Fort A.P. Hill, VA AGENCY... limits and time of designation of restricted area R-6601, Fort A.P. Hill, VA. The U.S. Army requested... limits and increase the time of designation of restricted area R-6601, Fort A.P. Hill, VA, (77 FR 35308...

Antimicrobial preservatives induce aggregation of interferon alpha-2a: The order in which preservatives induce protein aggregation is independent of the protein

PubMed Central

Bis, Regina L.; Mallela, Krishna M.G.

2014-01-01

Antimicrobial preservatives (APs) are included in liquid multi-dose protein formulations to combat the growth of microbes and bacteria. These compounds have been shown to cause protein aggregation, which leads to serious immunogenic and toxic side-effects in patients. Our earlier work on a model protein cytochrome c (Cyt c) demonstrated that APs cause protein aggregation in a specific manner. The aim of this study is to validate the conclusions obtained from our model protein studies on a pharmaceutical protein. Interferon α-2a (IFNA2) is available as a therapeutic treatment for numerous immune-compromised disorders including leukemia and hepatitis c, and APs have been used in its multi-dose formulation. Similar to Cyt c, APs induced IFNA2 aggregation, demonstrated by the loss of soluble monomer and increase in solution turbidity. The extent of IFNA2 aggregation increased with the increase in AP concentration. IFNA2 aggregation also depended on the nature of AP, and followed the order m-cresol > phenol > benzyl alcohol > phenoxyethanol. This specific order exactly matched with that observed for the model protein Cyt c. These and previously published results on antibodies and other recombinant proteins suggest that the general mechanism by which APs induce protein aggregation may be independent of the protein. PMID:24974985

Antimicrobial preservatives induce aggregation of interferon alpha-2a: the order in which preservatives induce protein aggregation is independent of the protein.

PubMed

Bis, Regina L; Mallela, Krishna M G

2014-09-10

Antimicrobial preservatives (APs) are included in liquid multi-dose protein formulations to combat the growth of microbes and bacteria. These compounds have been shown to cause protein aggregation, which leads to serious immunogenic and toxic side-effects in patients. Our earlier work on a model protein cytochrome c (Cyt c) demonstrated that APs cause protein aggregation in a specific manner. The aim of this study is to validate the conclusions obtained from our model protein studies on a pharmaceutical protein. Interferon α-2a (IFNA2) is available as a therapeutic treatment for numerous immune-compromised disorders including leukemia and hepatitis C, and APs have been used in its multi-dose formulation. Similar to Cyt c, APs induced IFNA2 aggregation, demonstrated by the loss of soluble monomer and increase in solution turbidity. The extent of IFNA2 aggregation increased with the increase in AP concentration. IFNA2 aggregation also depended on the nature of AP, and followed the order m-cresol>phenol>benzyl alcohol>phenoxyethanol. This specific order exactly matched with that observed for the model protein Cyt c. These and previously published results on antibodies and other recombinant proteins suggest that the general mechanism by which APs induce protein aggregation may be independent of the protein. Copyright © 2014 Elsevier B.V. All rights reserved.

Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons

PubMed Central

Zhong, Ping; Yan, Zhen

2016-01-01

Dopamine D4 receptor (D4R), which is strongly linked to neuropsychiatric disorders, such as attention-deficit hyperactivity disorder and schizophrenia, is highly expressed in pyramidal neurons and GABAergic interneurons in prefrontal cortex (PFC). In this study, we examined the impact of D4R on the excitability of these 2 neuronal populations. We found that D4R activation decreased the frequency of spontaneous action potentials (sAPs) in PFC pyramidal neurons, whereas it induced a transient increase followed by a decrease of sAP frequency in PFC parvalbumin-positive (PV+) interneurons. D4R activation also induced distinct effects in both types of PFC neurons on spontaneous excitatory and inhibitory postsynaptic currents, which drive the generation of sAP. Moreover, dopamine substantially decreased sAP frequency in PFC pyramidal neurons, but markedly increased sAP frequency in PV+ interneurons, and both effects were partially mediated by D4R activation. In the phencyclidine model of schizophrenia, the decreasing effect of D4R on sAP frequency in both types of PFC neurons was attenuated, whereas the increasing effect of D4R on sAP in PV+ interneurons was intact. These results suggest that D4R activation elicits distinct effects on synaptically driven excitability in PFC projection neurons versus fast-spiking interneurons, which are differentially altered in neuropsychiatric disorder-related conditions. PMID:25146372

Effects of aluminum and iron nanoparticle additives on composite AP/HTPB solid propellant regression rate

NASA Astrophysics Data System (ADS)

Styborski, Jeremy A.

This project was started in the interest of supplementing existing data on additives to composite solid propellants. The study on the addition of iron and aluminum nanoparticles to composite AP/HTPB propellants was conducted at the Combustion and Energy Systems Laboratory at RPI in the new strand-burner experiment setup. For this study, a large literature review was conducted on history of solid propellant combustion modeling and the empirical results of tests on binders, plasticizers, AP particle size, and additives. The study focused on the addition of nano-scale aluminum and iron in small concentrations to AP/HTPB solid propellants with an average AP particle size of 200 microns. Replacing 1% of the propellant's AP with 40-60 nm aluminum particles produced no change in combustive behavior. The addition of 1% 60-80 nm iron particles produced a significant increase in burn rate, although the increase was lesser at higher pressures. These results are summarized in Table 2. The increase in the burn rate at all pressures due to the addition of iron nanoparticles warranted further study on the effect of concentration of iron. Tests conducted at 10 atm showed that the mean regression rate varied with iron concentration, peaking at 1% and 3%. Regardless of the iron concentration, the regression rate was higher than the baseline AP/HTPB propellants. These results are summarized in Table 3.

Effects of gamma irradiation on cell-wall constituents of some agricultural residues

NASA Astrophysics Data System (ADS)

Al-Masri, M. R.; Zarkawi, M.

1994-12-01

The effects of 150 kilogray (kGy) of γ irradiation on cell-wall constituents of cottonwood (CW), lentils straw (LS), apple pruning products (AP) and olive cake (OC) were investigated. Samples were irradiated by γ irradiation at a dose level of 150 kGy under identical conditions of temperature and humidity and analyzed for crude fibre (CF), neutral-detergent fibre (NDF), acid detergent fibre (ADF) and acid-detergent lignin (ADL). The results indicate that γ irradiation decreased CF contents by about 29% for CW, LS and AP and by 17% for OC. NDF values were also decreased by about 4% for CW and OC, and by about 12% for LS and AP. γ Irradiation treatment also decreased ADF values only for CW by 8%. ADL contents decreased by 8% for CW and 5% for OC with no effects for LS and AP. The percentage of cellulose (CL): CF ratio increased by 30, 34, 38 and 20% for CW, LS, AP and OC, respectively. Also, the percentage of hemicellulose (HCL): CF increased by 57% for CW and 16% for OC and decreased by 7% for LS and AP. The percentage of HCL: ADL increased by 22% for CW but decreased by 33% for LS and AP with no changes for OC. There were no changes in CL: ADL ratio for all residues.

Effects of the Mitochondria-Targeted Antioxidant Mitoquinone in Murine Acute Pancreatitis

PubMed Central

Wen, Li; Szatmary, Peter; Mukherjee, Rajarshi; Armstrong, Jane; Chvanov, Michael; Tepikin, Alexei V.; Murphy, Michael P.; Sutton, Robert; Criddle, David N.

2015-01-01

Although oxidative stress has been strongly implicated in the development of acute pancreatitis (AP), antioxidant therapy in patients has so far been discouraging. The aim of this study was to assess potential protective effects of a mitochondria-targeted antioxidant, MitoQ, in experimental AP using in vitro and in vivo approaches. MitoQ blocked H2O2-induced intracellular ROS responses in murine pancreatic acinar cells, an action not shared by the control analogue dTPP. MitoQ did not reduce mitochondrial depolarisation induced by either cholecystokinin (CCK) or bile acid TLCS, and at 10 µM caused depolarisation per se. Both MitoQ and dTPP increased basal and CCK-induced cell death in a plate-reader assay. In a TLCS-induced AP model MitoQ treatment was not protective. In AP induced by caerulein hyperstimulation (CER-AP), MitoQ exerted mixed effects. Thus, partial amelioration of histopathology scores was observed, actions shared by dTPP, but without reduction of the biochemical markers pancreatic trypsin or serum amylase. Interestingly, lung myeloperoxidase and interleukin-6 were concurrently increased by MitoQ in CER-AP. MitoQ caused biphasic effects on ROS production in isolated polymorphonuclear leukocytes, inhibiting an acute increase but elevating later levels. Our results suggest that MitoQ would be inappropriate for AP therapy, consistent with prior antioxidant evaluations in this disease. PMID:25878403

Effects of the mitochondria-targeted antioxidant mitoquinone in murine acute pancreatitis.

PubMed

Huang, Wei; Cash, Nicole; Wen, Li; Szatmary, Peter; Mukherjee, Rajarshi; Armstrong, Jane; Chvanov, Michael; Tepikin, Alexei V; Murphy, Michael P; Sutton, Robert; Criddle, David N

2015-01-01

Although oxidative stress has been strongly implicated in the development of acute pancreatitis (AP), antioxidant therapy in patients has so far been discouraging. The aim of this study was to assess potential protective effects of a mitochondria-targeted antioxidant, MitoQ, in experimental AP using in vitro and in vivo approaches. MitoQ blocked H2O2-induced intracellular ROS responses in murine pancreatic acinar cells, an action not shared by the control analogue dTPP. MitoQ did not reduce mitochondrial depolarisation induced by either cholecystokinin (CCK) or bile acid TLCS, and at 10 µM caused depolarisation per se. Both MitoQ and dTPP increased basal and CCK-induced cell death in a plate-reader assay. In a TLCS-induced AP model MitoQ treatment was not protective. In AP induced by caerulein hyperstimulation (CER-AP), MitoQ exerted mixed effects. Thus, partial amelioration of histopathology scores was observed, actions shared by dTPP, but without reduction of the biochemical markers pancreatic trypsin or serum amylase. Interestingly, lung myeloperoxidase and interleukin-6 were concurrently increased by MitoQ in CER-AP. MitoQ caused biphasic effects on ROS production in isolated polymorphonuclear leukocytes, inhibiting an acute increase but elevating later levels. Our results suggest that MitoQ would be inappropriate for AP therapy, consistent with prior antioxidant evaluations in this disease.

Cardiovascular regulation in humans in response to oscillatory lower body negative pressure

NASA Technical Reports Server (NTRS)

Levenhagen, D. K.; Evans, J. M.; Wang, M.; Knapp, C. F.

1994-01-01

The frequency response characteristics of human cardiovascular regulation during hypotensive stress have not been determined. We therefore exposed 10 male volunteers to seven frequencies (0.004-0.1 Hz) of oscillatory lower body negative pressure (OLBNP; 0-50 mmHg). Fourier spectra of arterial pressure (AP), central venous pressure (CVP), stroke volume (SV), cardiac output (CO), heart rate (HR), and total peripheral resistance (TPR) were determined and first harmonic mean, amplitude, and phase angles with respect to OLBNP are presented. AP was relatively well regulated as demonstrated by small oscillations in half amplitude (3.5 mmHg) that were independent of OLBNP frequency and similar to unstressed control spectra. Due to the biomechanics of the system, the magnitudes of oscillations in calf circumference (CC) and CVP decreased with increasing frequency; therefore, we normalized responses by these indexes of the fluid volume shifted. The ratios of oscillations in AP to oscillations in CC increased by an order of magnitude, whereas oscillations in CVP to oscillations in CC and oscillations in AP to oscillations in CVP both tripled between 0.004 and 0.1 Hz. Therefore, even though the amount of fluid shifted by OLBNP decreased with increasing frequency, the magnitude of both CVP and AP oscillations per volume of fluid shifted increased (peaking at 0.08 Hz). The phase relationships between variables, particularly the increasing lags in SV and TPR, but not CVP, indicated that efferent responses with lags of 5-6 s could account for the observed responses. We conclude that, at frequencies below 0.02 Hz, the neural system of humans functioned optimally in regulating AP; OLBNP-induced decreases in SV (by as much as 50%) were counteracted by appropriate oscillations in HR and TPR responses. As OLBNP frequency increased, SV, TPR, and HR oscillations increasingly lagged the input and became less optimally timed for AP regulation.

Cementum structure in Beluga whale teeth

DOE PAGES

Stock, S. R.; Finney, L. A.; Telser, A.; ...

2016-11-09

We report that a large fraction of the volume of Beluga whale (Delphinapterus leucas) teeth consists of cementum, a mineralized tissue which grows throughout the life of the animal and to which the periodontal ligaments attach. Annular growth bands or growth layer groups (GLGs) form within Beluga cementum, and this study investigates GLG structure using X-ray fluorescence mapping and X-ray diffraction mapping with microbeams of synchrotron radiation. The Ca and Zn fluorescent intensities and carbonated hydroxyapatite (cAp) diffracted intensities rise and fall together and match the light-dark bands visible in transmitted light micrographs. Within the bands of maximum Ca andmore » Zn intensity, the ratio of Zn to Ca is slightly higher than in the minima bands. Further, the GLG cAp, Ca and Zn modulation is preserved throughout the cementum for durations >25 year.« less

Influence of diadenosine tetraphosphate (Ap4A) on lipid metabolism.

PubMed

Rüsing, D; Verspohl, E J

2004-01-01

Diadenosine polyphosphates (Ap(x)A) are physiologically released and may be partly involved in the pathogenesis of diabetes mellitus. Ap(4)A (diadenosine tetraphosphate) leads to an increase in blood glucose while it decreases insulin levels in plasma. A possible link between Ap(x)A and diabetes mellitus-associated diseases such as insulin resistance and hyperlipidemia (plasma free fatty acids, cholesterol and its biosynthesis, triacylglycerols) has not been investigated yet. Parameters such as free fatty acid and cholesterol content in blood were determined enzymically. The biosynthesis of cholesterol and triacylglycerols was determined in HepG2 cells using the radioactive precursor [(14)C]-acetate and by using gas chromatography. Plasma free fatty acids were significantly decreased 5 and 10 min after an Ap(4)A bolus (0.75 mg kg(-1) b.w.) given to rats. Plasma cholesterol was reduced 5 and 60 min after Ap(4)A administration. LPDS (lipoprotein-deficient serum)-stimulated cholesterol biosynthesis in HepG2 cells was significantly reduced after 1 h incubation with Ap(4)A. Triacylglycerol (TAG) biosynthesis in HepG2 cells was not significantly influenced by Ap(4)A; there was just a tendency for a concentration-dependent decrease in TAG levels. In conclusion Ap(4)A as a diabetogenetic compound is not likely to be responsible for the development of insulin resistance or of hyperlipidemia. Parameters such as free fatty acids, cholesterol and triacylglycerols are not elevated by Ap(4)A, but are even decreased. Ap(4)A seems to be involved in the development of diabetes mellitus by increasing blood glucose and decreasing plasma insulin as shown earlier, but not in diabetes mellitus-associated diseases such as insulin resistance or hyperlipidemia.

4-aminopyridine, a Kv channel antagonist, prevents apoptosis of rat cerebellar granule neurons.

PubMed

Hu, Chang-Long; Liu, Zheng; Zeng, Xi-Min; Liu, Zi-Qiang; Chen, Xian-Hua; Zhang, Zhi-Hong; Mei, Yan-Ai

2006-09-01

Compelling evidence indicates that excessive potassium (K+) efflux and intracellular K+ depletion are the key early steps in apoptosis. Previously, we reported that apoptosis of cerebellar granule neurons induced by incubation in low-K+ (5 mM) and serum-free medium was associated with an increase in A-type transient inactivation of K+ channel current (IA) amplitude and modulation of channels' gating properties. Here, we showed that a classic K+ channel blocker, 4-aminopyradine (4-AP), significantly inhibited IA amplitude in a concentration-dependent manner (reduction of current by 10 microM and 10 mM 4-AP was 11.4+/-1.3% and 72.2+/-3.3%, respectively). Moreover, 4-AP modified the steady-state activation and inactivation kinetics of IA channels, such that the activation and inactivation curves were shifted to the right about 20 mV and 17 mV, respectively. Fluorescence staining showed that 4-AP dramatically increased the viability of cells undergoing apoptosis in a dose-dependent manner. That is, while 5 mM 4-AP was present, cell viability was 84.9+/-5.2%. Consistent with the cell viability analysis, internucleosomal DNA fragmentation by gel electrophoresis analysis showed that 5 mM 4-AP also protected against neuronal apoptosis. Furthermore, 4-AP significantly inhibited cytochrome c release and caspase-3 activity induced by low-K+/serum-free incubation. Finally, current-clamp analysis indicated that 5 mM 4-AP did not significantly depolarize the membrane potential. These results suggest that 4-AP has robust neuroprotective effects on apoptotic granule cells. The neuroprotective effect of 4-AP is likely not due to membrane depolarization, but rather that 4-AP may modulate the gating properties of IA channels in an anti-apoptotic manner.

A local difference in Hedgehog signal transduction increases mechanical cell bond tension and biases cell intercalations along the Drosophila anteroposterior compartment boundary.

PubMed

Rudolf, Katrin; Umetsu, Daiki; Aliee, Maryam; Sui, Liyuan; Jülicher, Frank; Dahmann, Christian

2015-11-15

Tissue organization requires the interplay between biochemical signaling and cellular force generation. The formation of straight boundaries separating cells with different fates into compartments is important for growth and patterning during tissue development. In the developing Drosophila wing disc, maintenance of the straight anteroposterior (AP) compartment boundary involves a local increase in mechanical tension at cell bonds along the boundary. The biochemical signals that regulate mechanical tension along the AP boundary, however, remain unknown. Here, we show that a local difference in Hedgehog signal transduction activity between anterior and posterior cells is necessary and sufficient to increase mechanical tension along the AP boundary. This difference in Hedgehog signal transduction is also required to bias cell rearrangements during cell intercalations to keep the characteristic straight shape of the AP boundary. Moreover, severing cell bonds along the AP boundary does not reduce tension at neighboring bonds, implying that active mechanical tension is upregulated, cell bond by cell bond. Finally, differences in the expression of the homeodomain-containing protein Engrailed also contribute to the straight shape of the AP boundary, independently of Hedgehog signal transduction and without modulating cell bond tension. Our data reveal a novel link between local differences in Hedgehog signal transduction and a local increase in active mechanical tension of cell bonds that biases junctional rearrangements. The large-scale shape of the AP boundary thus emerges from biochemical signals inducing patterns of active tension on cell bonds. © 2015. Published by The Company of Biologists Ltd.

Regulation of rat mesangial cell growth by diadenosine phosphates.

PubMed Central

Heidenreich, S; Tepel, M; Schlüter, H; Harrach, B; Zidek, W

1995-01-01

The newly recognized human endogenous vasoconstrictive dinucleotides, diadenosine pentaphosphate (AP5A) and diadenosine hexaphosphate (AP6A), were tested for growth stimulatory effects in rat mesangial cells (MC). Both AP5A and AP6A stimulated growth in micromolar concentrations. The growth stimulatory effect exceeded that of ATP, alpha,beta-methylene ATP, adenosine 5'-O-(3-thio)triphosphate and UTP. Both diadenosine phosphates potentiated the growth response to platelet-derived growth factor, but not to insulin-like growth factor-1. To further elucidate the site of action in the cell cycle, RNA and protein synthesis were assessed. AP5 and AP6A stimulated protein synthesis, but not RNA formation. Furthermore, both agents increased cytosolic free Ca2+ concentration. It is concluded that AP5A and AP6A may play a regulatory role in MC growth as progression factors and possibly modify MC proliferation in glomerular disease. PMID:7769127

Diadenosine polyphosphates release by human corneal epithelium.

PubMed

Carracedo, Gonzalo; Guzman-Aranguez, Ana; Loma, Patricia; Pintor, Jesús

2013-08-01

Diadenosine polyphosphates are a type of dinucleotides that have been detected in rabbit and human tears. However, their origin and their mechanism of release have not been fully elucidated. In this work we investigated whether the dinucleotides Ap4A and Ap5A can be released from human corneal epithelia as a consequence of shear stress stimuli. In in vitro experiments, concentrations of Ap4A and Ap5A before mechanical stimulus of stratified human corneal epithelial cells were 3.18 ± 0.43 nM and 0.81 ± 0.13 nM, respectively. After shear stimulation, concentrations significantly increased to 12.01 ± 2.19 nM for Ap4A and 2.83 ± 0.41 nM for Ap5A. No significant differences in lactate dehydrogenase activity were detected between non-stimulated stratified human corneal epithelial cells and cells exposed to mechanical shear-stress, indicating that the rise of dinucleotide levels was not due to cell lysis. In in vivo experiments, individuals subjected to a rise in blinking frequency showed a significant increase of Ap4A (∼25-fold when experiment was performed without anaesthetic and 75-fold with anaesthetic) and Ap5A concentration in tears (∼50-fold when experiment was performed without anaesthetic and 125-fold with anaesthetic). Shear-stress stimuli induces Ap4A and Ap5A release from human corneal epithelium, thus explaining the origin of these relevant compounds for the ocular surface biochemistry and physiology. Copyright © 2013 Elsevier Ltd. All rights reserved.

Glossary for the implementation of Health in All Policies (HiAP).

PubMed

Freiler, Alix; Muntaner, Carles; Shankardass, Ketan; Mah, Catherine L; Molnar, Agnes; Renahy, Emilie; O'Campo, Patricia

2013-12-01

Health in All Policies (HiAP) is becoming increasingly popular as a governmental strategy to improve population health by coordinating action across health and non-health sectors. A variety of intersectoral initiatives may be used in HiAP that frame health determinants as the bridge between policies and health outcomes. The purpose of this glossary is to present concepts and terms useful in understanding the implementation of HiAP as a cross-sectoral policy. The concepts presented here were applied and elaborated over the course of case studies of HiAP in multiple jurisdictions, which used key informant interviews and the systematic review of literature to study the implementation of specific HiAP initiatives.

Dendritic Properties Control Energy Efficiency of Action Potentials in Cortical Pyramidal Cells

PubMed Central

Yi, Guosheng; Wang, Jiang; Wei, Xile; Deng, Bin

2017-01-01

Neural computation is performed by transforming input signals into sequences of action potentials (APs), which is metabolically expensive and limited by the energy available to the brain. The metabolic efficiency of single AP has important consequences for the computational power of the cell, which is determined by its biophysical properties and morphologies. Here we adopt biophysically-based two-compartment models to investigate how dendrites affect energy efficiency of APs in cortical pyramidal neurons. We measure the Na+ entry during the spike and examine how it is efficiently used for generating AP depolarization. We show that increasing the proportion of dendritic area or coupling conductance between two chambers decreases Na+ entry efficiency of somatic AP. Activating inward Ca2+ current in dendrites results in dendritic spike, which increases AP efficiency. Activating Ca2+-activated outward K+ current in dendrites, however, decreases Na+ entry efficiency. We demonstrate that the active and passive dendrites take effects by altering the overlap between Na+ influx and internal current flowing from soma to dendrite. We explain a fundamental link between dendritic properties and AP efficiency, which is essential to interpret how neural computation consumes metabolic energy and how biophysics and morphologies contribute to such consumption. PMID:28919852

Dendritic Properties Control Energy Efficiency of Action Potentials in Cortical Pyramidal Cells.

PubMed

Yi, Guosheng; Wang, Jiang; Wei, Xile; Deng, Bin

2017-01-01

Neural computation is performed by transforming input signals into sequences of action potentials (APs), which is metabolically expensive and limited by the energy available to the brain. The metabolic efficiency of single AP has important consequences for the computational power of the cell, which is determined by its biophysical properties and morphologies. Here we adopt biophysically-based two-compartment models to investigate how dendrites affect energy efficiency of APs in cortical pyramidal neurons. We measure the Na + entry during the spike and examine how it is efficiently used for generating AP depolarization. We show that increasing the proportion of dendritic area or coupling conductance between two chambers decreases Na + entry efficiency of somatic AP. Activating inward Ca 2+ current in dendrites results in dendritic spike, which increases AP efficiency. Activating Ca 2+ -activated outward K + current in dendrites, however, decreases Na + entry efficiency. We demonstrate that the active and passive dendrites take effects by altering the overlap between Na + influx and internal current flowing from soma to dendrite. We explain a fundamental link between dendritic properties and AP efficiency, which is essential to interpret how neural computation consumes metabolic energy and how biophysics and morphologies contribute to such consumption.

Heart failure with preserved ejection fraction: comparison of patients with and without angina pectoris (from the Duke Databank for Cardiovascular Disease).

PubMed

Mentz, Robert J; Broderick, Samuel; Shaw, Linda K; Fiuzat, Mona; O'Connor, Christopher M

2014-01-28

This study investigated the characteristics and outcomes of patients with heart failure with preserved ejection fraction (HFpEF) and angina pectoris (AP). AP is a predictor of adverse events in patients with heart failure with reduced EF. The implications of AP in HFpEF are unknown. We analyzed HFpEF patients (EF ≥50%) who underwent coronary angiography at Duke University Medical Center from 2000 through 2010 with and without AP in the previous 6 weeks. Time to first event was examined using Kaplan-Meier methods for the primary endpoint of death/myocardial infarction (MI)/revascularization/stroke (i.e., major adverse cardiac events [MACE]) and secondary endpoints of death/MI/revascularization, death/MI/stroke, death/MI, death, and cardiovascular death/cardiovascular hospitalization. In the Duke Databank, 3,517 patients met criteria for inclusion and 1,402 (40%) had AP. Those with AP were older with more comorbidities and prior revascularization compared with non-AP patients. AP patients more often received beta-blockers, angiotensin-converting enzyme inhibitors, nitrates, and statins (all p < 0.05). In unadjusted analysis, AP patients had increased MACE and death/MI/revascularization (both p < 0.001), lower rates of death and death/MI (both p < 0.05), and similar rates of death/MI/stroke and cardiovascular death/cardiovascular hospitalization (both p > 0.1). After multivariable adjustment, those with AP remained at increased risk for MACE (hazard ratio [HR]: 1.30, 95% confidence interval [CI]: 1.17 to 1.45) and death/MI/revascularization (HR: 1.29, 95% CI: 1.15 to 1.43), but they were at similar risk for other endpoints (p > 0.06). AP in HFpEF patients with a history of coronary artery disease is common despite medical therapy and is independently associated with increased MACE due to revascularization with similar risk of death, MI, and hospitalization. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Prevalence of apical periodontitis and endodontic treatment in a Kosovar adult population.

PubMed

Kamberi, Blerim; Hoxha, Veton; Stavileci, Miranda; Dragusha, Edmond; Kuçi, Astrit; Kqiku, Lumnije

2011-11-29

Despite numerous studies on the prevalence of apical periodontitis (AP) and endodontic treatment in diverse geographical populations, there are currently no data on the prevalence of these conditions in populations of adults native to Kosovo. Therefore, little is known about how widespread these conditions are, and whether there is any correlation between root canal treatment and AP. The purpose of our research was to address this anomaly by investigating AP and endodontic treatment in an adult Kosovar population based on radiographic examination. The sample used for this study consisted of randomly selected individuals referred to the University Dentistry Clinical Center of Kosovo in the years 2006-2007. Orthopantomographs of 193 patients were evaluated. The periapical status of all teeth (with the exception of third molars) was examined according to Ørstavik's Periapical Index. The quality of the root canal filling was rated as 'adequate' or 'inadequate' based on whether all canals were filled, the depth of fill relative to the radiographic apex and the quality of compaction (absence/presence of voids). Data were analyzed statistically using the Chi-square test and calculation of odds ratios. Out of 4131 examined teeth, the prevalence of apical periodontitis (AP) and endodontic treatment was 12.3% and 2.3%, respectively. Of 95 endodontically-treated teeth, 46.3% were associated with AP. The prevalence of AP increased with age. The prevalence in subjects aged over 60 years old (20.2%) was higher than in other age groups. A statistically significant difference was found for the frequency of endodontically-treated teeth associated with AP in the 40-49 year age group (P < 0.001). Of some concern was the discovery that only 30.5% of the endodontically-treated teeth examined met the criteria of an acceptable root canal filling. Inadequately root-filled teeth were associated with an increased AP risk. The prevalence of AP and the frequency of endodontically-treated teeth with AP in this Kosovar population are higher than those found in other countries. Inadequate root canal fillings were associated with an increased prevalence of AP.

The Earlier the Better? Taking the AP® in 10th Grade. Research Report No. 2012-10

ERIC Educational Resources Information Center

Rodriguez, Awilda; McKillip, Mary E. M.; Niu, Sunny X.

2013-01-01

In this report, the authors examine the impact of scoring a 1 or 2 on an AP® Exam in 10th grade on later AP Exam participation and performance. As access to AP courses increases within and across schools, a growing number of students are taking AP courses and exams in the earlier grades of high school. Using a matched sample of AP and no-AP…

Systematic characterization of the ionic basis of rabbit cellular electrophysiology using two ventricular models.

PubMed

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.

Factor Xa Mediates Calcium Flux in Endothelial Cells and is Potentiated by Igg From Patients With Lupus and/or Antiphospholipid Syndrome.

PubMed

Artim-Esen, Bahar; Smoktunowicz, Natalia; McDonnell, Thomas; Ripoll, Vera M; Pericleous, Charis; Mackie, Ian; Robinson, Eifion; Isenberg, David; Rahman, Anisur; Ioannou, Yiannis; Chambers, Rachel C; Giles, Ian

2017-09-07

Factor (F) Xa reactive IgG isolated from patients with antiphospholipid syndrome (APS) display higher avidity binding to FXa with greater coagulant effects compared to systemic lupus erythematosus (SLE) non APS IgG. FXa signalling via activation of protease-activated receptors (PAR) leads to increased intracellular calcium (Ca 2+ ). Therefore, we measured alterations in Ca 2+ levels in human umbilical vein endothelial cells (HUVEC) following FXa-mediated PAR activation and investigated whether FXa reactive IgG from patients with APS or SLE/APS- alter these responses. We observed concentration-dependent induction of Ca 2+ release by FXa that was potentiated by APS-IgG and SLE/APS- IgG compared to healthy control subjects' IgG, and FXa alone. APS-IgG and SLE/APS- IgG increased FXa mediated NFκB signalling and this effect was fully-retained in the affinity purified anti-FXa IgG sub-fraction. Antagonism of PAR-1 and PAR-2 reduced FXa-induced Ca 2+ release. Treatment with a specific FXa inhibitor, hydroxychloroquine or fluvastatin significantly reduced FXa-induced and IgG-potentiated Ca 2+ release. In conclusion, PAR-1 and PAR-2 are involved in FXa-mediated intracellular Ca 2+ release in HUVEC and FXa reactive IgG from patients with APS and/or SLE potentiate this effect. Further work is required to explore the potential use of IgG FXa reactivity as a novel biomarker to stratify treatment with FXa inhibitors in these patients.

Enzyme induction in neonates after fetal exposure to antiepileptic drugs

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

Rating, D.; Jaeger-Roman, E.; Nau, H.

1983-01-01

The /sup 13/C-AP breath test is shown to be a convenient, noninvasive method to monitor velocity and capacity of P450-dependent AP N-demethylation in infancy and childhood. According to /sup 13/C-AP breath tests, neonates have a very low capacity to eliminate /sup 13/CO/sub 2/, which is only 15 to 21% of the activity in adults. During the first year of life AP N-demethylation increases to reach its maximum at about 2 years; afterwards a slight decrease occurs. In 25 neonates exposed prenatally to different antiepileptic drugs /sup 13/C-AP breath test was efficiently used to prove that cytochrome AP N-demethylation was considerablymore » stimulated. After primidone/phenobarbitone, especially in combination with phenytoin, /sup 13/C elimination reaches and even surpasses the range for older children. Valproate exposure during fetal life is not consistently followed by a significant increase in AP N-demethylation. The enzyme induction demonstrated by /sup 13/C-AP breath test was often accompanied by accelerated metabolic clearance and shortened half-life times of transplacentally acquired antiepileptic drugs. There was good agreement between /sup 13/C-AP breath tests and pharmacokinetic data for primidone/phenobarbitone but not for phenytoin. In contrast, in the case of phenytoin exposure during pregnancy the pharmacokinetic parameters and the /sup 13/C breath test data will transport very different informations about enzyme induction in these neonates.« less

Diadenosine tetraphosphate reduces toxicity caused by high-dose methamphetamine administration.

PubMed

Harvey, Brandon K; Chou, Jenny; Shen, Hui; Hoffer, Barry J; Wang, Yun

2009-05-01

Diadenosine tetraphosphate (AP(4)A), two adenosine moieties bridged by four phosphates, is an endogenous purinergic ligand found in brain. Previous studies have shown that AP(4)A reduced neurodegeneration caused by the dopaminergic neurotoxin 6-hydroxydopamine in rat striatum and substantia nigra. The purpose of this study was to determine whether AP(4)A is protective against methamphetamine (MA)-mediated toxicity. Primary neuronal cultures were prepared from rat embryonic (E14-E15) ventral mesencephalic tissue. Cultures treated with 2mM MA exhibited decreased tyrosine hydroxylase (TH) immunoreactivity and increased cleaved caspase-3 immunoreactivity and TUNEL labeling. All these changes were lessened by pretreatment with AP(4)A. The protective effect of AP(4)A was also found in vivo. Adult Sprague-Dawley rats were injected with AP(4)A (25 microg/20 microl) or vehicle intracerebroventricularly followed by 4 doses of MA (5 or 10 mg/kg), given subcutaneously every 2h. Administration of MA reduced locomotor activity 1 day after injection, which was significantly antagonized by the pretreatment with AP(4)A. Using immunohistochemical analysis, TH fiber density at the substantia nigra pars reticulata was found reduced while cleaved caspase-3 immunoreactivity in striatum was increased after MA treatment; these responses were also significantly antagonized by AP(4)A. Taken together, our data show that AP(4)A has protective effects against MA-mediated toxicity both in vitro and in vivo. The mechanism of action involves suppression of MA-induced apoptosis.

Diadenosine Tetraphosphate Reduces Toxicity caused by High-Dose Methamphetamine Administration

PubMed Central

Harvey, Brandon K.; Chou, Jenny; Shen, Hui; Hoffer, Barry J.; Wang, Yun

2009-01-01

Diadenosine tetraphosphate (AP4A), two adenosine moieties bridged by four phosphates, is an endogenous purinergic ligand found in brain. Previous studies have shown that AP4A reduced neurodegeneration caused by the dopaminergic neurotoxin 6-hydroxydopamine in rat striatum and substantia nigra. The purpose of this study was to determine whether AP4A is protective against methamphetamine (MA) –mediated toxicity. Primary neuronal cultures were prepared from rat embryonic (E14- E15) ventral mesencephalic tissue. Cultures treated with 2 mM MA exhibited decreased tyrosine hydroxylase (TH) immunoreactivity and increased cleaved caspase-3 immunoreactivity and TUNEL labeling. All these changes were lessened by pretreatment with AP4A. The protective effect of AP4A was also found in vivo. Adult Sprague-Dawley rats were injected with AP4A (25 μg/ 20 μl) or vehicle intracerebroventricularly followed by 4 doses of MA (5 or 10 mg/ kg), given subcutaneously every two hours. Administration of MA reduced locomotor activity one day after injection, which was significantly antagonized by the pretreatment with AP4A. Using immunohistochemical analysis, TH fiber density at the substantia nigra pars reticulata was found reduced while cleaved caspase-3 immunoreactivity in striatum was increased after MA treatment; these responses were also significantly antagonized by AP4A. Taken together, our data show that AP4A has protective effects against MA-mediated toxicity both in vitro and in vivo. The mechanism of action involves suppression of MA -induced apoptosis. PMID:19442829

Dose- and time-dependent increase of lysosomal enzymes in embryonic cartilage in vitro after ionizing radiation

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

Cornelissen, M.; de Ridder, L.

Radiation doses of 20, 50 or 100 Gy caused the same time related decrease for RNA and proteoglycan (PG) synthesis in embryonic cartilage in vitro (4 days culture). In this paper, participation of lysosomes in this radiation response is investigated. Therefore, we employ a cytochemical method using beta-glycerophosphate as substrate for acid phosphatase (AP) detection. Increase of AP was found 2 days after irradiation and increased during the whole culture period. The increase was more pronounced with a higher radiation dose. Stimulation of AP activity explains the observed radiation response of RNA and PG synthesis.

Timing and efficacy of Ca2+ channel activation in hippocampal mossy fiber boutons.

PubMed

Bischofberger, Josef; Geiger, Jörg R P; Jonas, Peter

2002-12-15

The presynaptic Ca2+ signal is a key determinant of transmitter release at chemical synapses. In cortical synaptic terminals, however, little is known about the kinetic properties of the presynaptic Ca2+ channels. To investigate the timing and magnitude of the presynaptic Ca2+ inflow, we performed whole-cell patch-clamp recordings from mossy fiber boutons (MFBs) in rat hippocampus. MFBs showed large high-voltage-activated Ca(2+) currents, with a maximal amplitude of approximately 100 pA at a membrane potential of 0 mV. Both activation and deactivation were fast, with time constants in the submillisecond range at a temperature of approximately 23 degrees C. An MFB action potential (AP) applied as a voltage-clamp command evoked a transient Ca2+ current with an average amplitude of approximately 170 pA and a half-duration of 580 microsec. A prepulse to +40 mV had only minimal effects on the AP-evoked Ca2+ current, indicating that presynaptic APs open the voltage-gated Ca2+ channels very effectively. On the basis of the experimental data, we developed a kinetic model with four closed states and one open state, linked by voltage-dependent rate constants. Simulations of the Ca2+ current could reproduce the experimental data, including the large amplitude and rapid time course of the current evoked by MFB APs. Furthermore, the simulations indicate that the shape of the presynaptic AP and the gating kinetics of the Ca2+ channels are tuned to produce a maximal Ca2+ influx during a minimal period of time. The precise timing and high efficacy of Ca2+ channel activation at this cortical glutamatergic synapse may be important for synchronous transmitter release and temporal information processing.

The right thalamus may play an important role in anesthesia-awakening regulation in frogs

PubMed Central

Fan, Yanzhu; Yue, Xizi; Xue, Fei; Brauth, Steven E.; Tang, Yezhong

2018-01-01

Background Previous studies have shown that the mammalian thalamus is a key structure for anesthesia-induced unconsciousness and anesthesia-awakening regulation. However, both the dynamic characteristics and probable lateralization of thalamic functioning during anesthesia-awakening regulation are not fully understood, and little is known of the evolutionary basis of the role of the thalamus in anesthesia-awakening regulation. Methods An amphibian species, the South African clawed frog (Xenopus laevis) was used in the present study. The frogs were immersed in triciane methanesulfonate (MS-222) for general anesthesia. Electroencephalogram (EEG) signals were recorded continuously from both sides of the telencephalon, diencephalon (thalamus) and mesencephalon during the pre-anesthesia stage, administration stage, recovery stage and post-anesthesia stage. EEG data was analyzed including calculation of approximate entropy (ApEn) and permutation entropy (PE). Results Both ApEn and PE values differed significantly between anesthesia stages, with the highest values occurring during the awakening period and the lowest values during the anesthesia period. There was a significant correlation between the stage durations and ApEn or PE values during anesthesia-awakening cycle primarily for the right diencephalon (right thalamus). ApEn and PE values for females were significantly higher than those for males. Discussion ApEn and PE measurements are suitable for estimating depth of anesthesia and complexity of amphibian brain activity. The right thalamus appears physiologically positioned to play an important role in anesthesia-awakening regulation in frogs indicating an early evolutionary origin of the role of the thalamus in arousal and consciousness in land vertebrates. Sex differences exist in the neural regulation of general anesthesia in frogs. PMID:29576980

Inhibitory Effect of Vascular Endothelial Growth Factor on the Slowly Activating Delayed Rectifier Potassium Current in Guinea Pig Ventricular Myocytes.

PubMed

Lin, Zhenhao; Xing, Wenlu; Gao, Chuanyu; Wang, Xianpei; Qi, Datun; Dai, Guoyou; Zhao, Wen; Yan, Ganxin

2018-01-26

Vascular endothelial growth factor (VEGF) exerts a number of beneficial effects on ischemic myocardium via its angiogenic properties. However, little is known about whether VEGF has a direct effect on the electrical properties of cardiomyocytes. In the present study, we investigated the effects of different concentrations of VEGF on delayed rectifier potassium currents (I K ) in guinea pig ventricular myocytes and their effects on action potential (AP) parameters. I K and AP were recorded by the whole-cell patch clamp method in ventricular myocytes. Cells were superfused with control solution or solution containing VEGF at different concentrations for 10 minutes before recording. Some ventricular myocytes were pretreated with a phosphatidylinositol 3-kinase inhibitor for 1 hour before the addition of VEGF. We found that VEGF inhibited the slowly activating delayed rectifier potassium current (I K s ) in a concentration-dependent manner (18.13±1.04 versus 12.73±0.34, n=5, P =0.001; 12.73±0.34 versus 9.05±1.20, n=5, P =0.036) and prolonged AP duration (894.5±36.92 versus 746.3±33.71, n=5, P =0.021). Wortmannin, a phosphatidylinositol 3-kinase inhibitor, eliminated these VEGF-induced effects. VEGF had no significant effect on the rapidly activating delayed rectifier potassium current (I K r ), resting membrane potential, AP amplitude, or maximal velocity of depolarization. VEGF inhibited I K s in a concentration-dependent manner through a phosphatidylinositol 3-kinase-mediated signaling pathway, leading to AP prolongation. The results indicate a promising therapeutic potential of VEGF in prevention of ventricular tachyarrhythmias under conditions of high sympathetic activity and ischemia. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Nutrient and Trace Metal Controls on Alkaline Phosphatase in the Subtropical Ocean: Insights from Bioassays and Gene Expression

NASA Astrophysics Data System (ADS)

Mahaffey, C.; Reynolds, S.; Davis, C. E.; Lohan, M. C.

2016-02-01

Phosphorus is an essential nutrient for all life on earth. In the ocean, the most bioavailable form of phosphorus is inorganic phosphate, but in the extensive subtropical gyres, phosphate concentrations can be chronically low in the surface ocean and limit biological activity. In response to phosphate limitation, organisms produce phosphohydrolytic enzymes, such as alkaline phosphatases (AP), that enable them to utilize the more replete dissolved organic phosphorus (DOP) pool to meet their cellular phosphorus demands. Synthesis of data from the surface ocean from 14 open ocean studies reveals an inverse hyperbolic relationship between phosphate and AP, where AP is significantly induced at phosphate concentrations below 50 nM and DOP concentrations decrease as AP increases. AP activity was significantly higher in the subtropical Atlantic compared to the subtropical Pacific Ocean, even over the same low phosphate concentration range (0 to 50 nM). While the phosphate concentration may have a first order control on the rates of AP, we demonstrate that other factors influence AP activity. AP are metalloenzymes and zinc and iron are co-factors of the AP proteins PhoA and PhoX, respectively. Using bioassay experiments, we show that the addition of Saharan dust and zinc significantly increases the rate of AP. To our knowledge, our results are the first direct field-based evidence that AP activity is limited by zinc in the subtropical ocean. In colonies of nitrogen fixer, Trichodesmium, we found enhanced expression of the phoA gene in a region of elevated zinc concentrations and enhanced expression of the phoX gene in a region of elevated iron concentrations around the intertropical convergence zone. Our study highlights the potential link between the phosphorus cycle and trace metals, specifically zinc and iron, and implies that there is potential for zinc-phosphorus and iron-phosphorus co-limitation in the ocean via AP.

Sulfate-activating enzymes of Penicillium chrysogenum. The ATP sulfurylase. adenosine 5'-phosphosulfate complex does not serve as a substrate for adenosine 5'-phosphosulfate kinase

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

Renosto, F.; Martin, R.L.; Segel, I.H.

1989-06-05

At a noninhibitory steady state concentration of adenosine 5'-phosphosulfate (APS), increasing the concentration of Penicillium chrysogenum ATP sulfurylase drives the rate of the APS kinase-catalyzed reaction toward zero. The result indicates that the ATP sulfurylase.APS complex does not serve as a substrate for APS kinase, i.e. there is no ''substrate channeling'' of APS between the two sulfate-activating enzymes. APS kinase had no effect on the (S)0.5 values, nH values, or maximum isotope trapping in the single turnover of ATP sulfurylase-bound (/sup 35/S)APS. Equimolar APS kinase (+/- MgATP or APS) also had no effect on the rate constants for the inactivationmore » of ATP sulfurylase by phenylglyoxal, diethylpyrocarbonate, or N-ethylmaleimide. Similarly, ATP sulfurylase (+/- ligands) had no effect on the inactivation of equimolar APS kinase by trinitrobenzene sulfonate, diethylpyrocarbonate, or heat. (The last promotes the dissociation of dimeric APS kinase to inactive monomers.) ATP sulfurylase also had no effect on the reassociation of APS kinase subunits at low temperature. The cumulative results suggest that the two sulfate activating enzymes do not associate to form a ''3'-phosphoadenosine 5'-phosphosulfate synthetase'' complex.« less

Stimulatory effect of exogenous diadenosine tetraphosphate on insulin and glucagon secretion in the perfused rat pancreas

PubMed Central

Silvestre, Ramona A; Rodríguez-Gallardo, Jovita; Egido, Eva M; Marco, José

1999-01-01

Diadenosine triphosphate (AP3A) and diadenosine tetraphosphate (AP4A) are released by various cells (e.g. platelets and chromaffin cells), and may act as extracellular messengers. In pancreatic B-cells, AP3A and AP4A are inhibitors of the ATP-regulated K+ channels, and glucose increases intracellular levels of both substances.We have studied the effect of exogenous AP3A and AP4A on insulin and glucagon secretion by the perfused rat pancreas.AP3A did not significantly modify insulin or glucagon release, whereas AP4A induced a prompt, short-lived insulin response (≈4 fold higher than basal value; P<0.05) in pancreases perfused at different glucose concentrations (3.2, 5.5 or 9 mM). AP4A-induced insulin release was abolished by somatostatin and by diazoxide. These two substances share the capacity to activate ATP-dependent K+ channels, suggesting that these channels are a potential target for AP4A in the B-cell.AP4A stimulated glucagon release at both 3.2 and 5.5 mM glucose. This effect was abolished by somatostatin.The results suggest that extracellular AP4A may play a physiological role in the control of insulin and glucagon secretion. PMID:10516664

Stimulatory effect of exogenous diadenosine tetraphosphate on insulin and glucagon secretion in the perfused rat pancreas.

PubMed

Silvestre, R A; Rodríguez-Gallardo, J; Egido, E M; Marco, J

1999-10-01

1. Diadenosine triphosphate (AP3A) and diadenosine tetraphosphate (AP4A) are released by various cells (e.g. platelets and chromaffin cells), and may act as extracellular messengers. In pancreatic B-cells, AP3A and AP4A are inhibitors of the ATP-regulated K+ channels, and glucose increases intracellular levels of both substances. 2. We have studied the effect of exogenous AP3A and AP4A on insulin and glucagon secretion by the perfused rat pancreas. 3. AP3A did not significantly modify insulin or glucagon release, whereas AP4A induced a prompt, short-lived insulin response ( approximately 4 fold higher than basal value; P<0.05) in pancreases perfused at different glucose concentrations (3.2, 5.5 or 9 mM). AP4A-induced insulin release was abolished by somatostatin and by diazoxide. These two substances share the capacity to activate ATP-dependent K+ channels, suggesting that these channels are a potential target for AP4A in the B-cell. 4. AP4A stimulated glucagon release at both 3.2 and 5.5 mM glucose. This effect was abolished by somatostatin. 5. The results suggest that extracellular AP4A may play a physiological role in the control of insulin and glucagon secretion.

Leaching of a copper flotation concentrate with ammonium persulfate in an autoclave system

NASA Astrophysics Data System (ADS)

Deniz Turan, M.; Soner Altundoğan, H.

2014-09-01

The leaching behavior of a copper flotation concentrate was investigated using ammonium persulfate (APS) in an autoclave system. The decomposition products of APS, active oxygen, and acidic medium were used to extract metals from the concentrate. Leaching experiments were performed to compare the availability of APS as an oxidizing agent for leaching of the concentrate under atmospheric conditions and in an autoclave system. Leaching temperature and APS concentration were found to be important parameters in both leaching systems. Atmospheric leaching studies showed that the metal extractions increased with the increase in APS concentration and temperature (up to 333 K). A similar tendency was determined in the autoclave studies up to 423 K. It was also determined that the metal extractions decreased at temperatures above 423 K due to the passivation of the particle surface by molten elemental sulfur. The results showed that higher copper extractions could be achieved using an autoclave system.

Risk of development of acute pancreatitis with pre-existing diabetes: a meta-analysis.

PubMed

Xue, Yuzheng; Sheng, Yingyue; Dai, Hong; Cao, Haiyan; Liu, Zongliang; Li, Zhaoshen

2012-09-01

It is well established that acute pancreatitis (AP) often causes diabetes mellitus. However, whether pre-existing diabetes is associated with the development of AP remains unknown. To clarify the association of pre-existing diabetes and the development of AP, we carried out a meta-analysis of observational studies. A computerized literature search was performed in MEDLINE (from 1 January 1966) and EMBASE (from 1 January 1974), through 31 January 2012. We also searched the reference lists of relevant articles. Summary relative risks with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q statistic and the I 2. A total of seven articles (10 523 incident cases of AP) were included in this meta-analysis. Analysis of seven studies indicated that, compared with nondiabetic individuals, diabetic individuals had a 92% increased risk of development of AP (95% CI 1.50-2.47). There was significant evidence of heterogeneity among these studies (P heterogeneity<0.001, I 2=93.0%). These increased risks were independent of alcohol use, gallstones, and hyperlipidemia. Although the current evidence supports a positive link between pre-existing diabetes and an increased risk of development of AP, additional studies, with a perfect design, are required before definitive conclusions can be drawn.

Remediation of lead-contaminated sediment by biochar-supported nano-chlorapatite: Accompanied with the change of available phosphorus and organic matters.

PubMed

Huang, Danlian; Deng, Rui; Wan, Jia; Zeng, Guangming; Xue, Wenjing; Wen, Xiaofeng; Zhou, Chengyun; Hu, Liang; Liu, Xigui; Xu, Piao; Guo, Xueying; Ren, Xiaoya

2018-04-15

Some rivers in China have been seriously contaminated due to the discharge of lead (Pb) smelting wastewater. In this study, biochar-supported nano-chlorapatite (BC-nClAP) was synthesized to immobilize Pb in contaminated sediment. The remediation effect of BC-nClAP on Pb-contaminated sediment was evaluated through batch experiments and the materials were characterized by x-ray diffraction, scanning electron microscope, Brunner-Emmet-Teller and electronic differential system. It was found that BC-nClAP can transform Pb effectively from labile fraction into stable fraction with a maximum transformation efficiency increasing to 94.1% after 30 days of treatment, and the stabilization efficiency of toxicity characteristic leaching procedure reached 100% only after 16 days of treatment. The content of available phosphorus (AP) in the sediments treated by BC-nClAP was much less than that treated by nClAP, which indicated a lower risk of eutrophication and suggested the dissolution-precipitation mechanism involved in Pb immobilization. BC-nClAP presented the best immobilization efficiency of Pb and the content of organic matters in BC-nClAP treated samples increased the most, thus the OM might play an important role during the Pb immobilization. Copyright © 2018 Elsevier B.V. All rights reserved.

Preventive effects of ACTICOA powder, a cocoa polyphenolic extract, on experimentally induced prostate hyperplasia in Wistar-Unilever rats.

PubMed

Bisson, Jean-François; Hidalgo, Sophie; Rozan, Pascale; Messaoudi, Michaël

2007-12-01

Plant extracts are useful in the management of benign prostatic hyperplasia (BPH). This study investigates whether ACTICOA (Barry Callebaut France, Louviers, France) powder (AP), a cocoa polyphenolic extract, could prevent prostate hyperplasia induced by testosterone propionate (TP) in rats. Male Wistar-Unilever rats were randomly divided in four groups of 12 rats: one negative control group receiving subcutaneous injections of corn oil and treated with vehicle and three groups injected subcutaneously with TP and treated with the vehicle (positive control) or AP at 24 (AP24) and 48 (AP48) mg/kg/day. Treatments were given orally and started 2 weeks before the induction of prostate hyperplasia. The influence of TP and AP on body weights and food and water consumption of rats was examined. On day 36, rats were sacrificed, and the prostates were removed, cleaned, and weighed. The prostate size ratio (prostate weight/rat body weight) was then calculated. TP significantly influenced the body weight gain of the rats and their food and water consumption, while AP at both doses tested reduced significantly these differences. TP significantly increased prostate size ratio (P < .001), and this induced increase was significantly inhibited in AP-treated rats in comparison with positive controls (P < .001) in a dose-dependent manner. We conclude that AP can prevent TP-induced prostate hyperplasia and therefore may be beneficial in the management of BPH.

New method for estimating clustering of DNA lesions induced by physical/chemical mutagens using fluorescence anisotropy.

PubMed

Akamatsu, Ken; Shikazono, Naoya; Saito, Takeshi

2017-11-01

We have developed a new method for estimating the localization of DNA damage such as apurinic/apyrimidinic sites (APs) on DNA using fluorescence anisotropy. This method is aimed at characterizing clustered DNA damage produced by DNA-damaging agents such as ionizing radiation and genotoxic chemicals. A fluorescent probe with an aminooxy group (AlexaFluor488) was used to label APs. We prepared a pUC19 plasmid with APs by heating under acidic conditions as a model for damaged DNA, and subsequently labeled the APs. We found that the observed fluorescence anisotropy (r obs ) decreases as averaged AP density (λ AP : number of APs per base pair) increases due to homo-FRET, and that the APs were randomly distributed. We applied this method to three DNA-damaging agents, 60 Co γ-rays, methyl methanesulfonate (MMS), and neocarzinostatin (NCS). We found that r obs -λ AP relationships differed significantly between MMS and NCS. At low AP density (λ AP  < 0.001), the APs induced by MMS seemed to not be closely distributed, whereas those induced by NCS were remarkably clustered. In contrast, the AP clustering induced by 60 Co γ-rays was similar to, but potentially more likely to occur than, random distribution. This simple method can be used to estimate mutagenicity of ionizing radiation and genotoxic chemicals. Copyright © 2017 Elsevier Inc. All rights reserved.

Lipopolysaccharide potentiates the effect of hepatocyte growth factor on hepatocyte replication in rats by augmenting AP-1 activity.

PubMed

Gao, C; Jokerst, R; Gondipalli, P; Cai, S R; Kennedy, S; Flye, M W; Ponder, K P

1999-12-01

The liver regenerates by replication of differentiated hepatocytes after damage or removal of part of the liver. Although several growth factors and signaling pathways are activated during regeneration, it is unclear as to which of these are essential for hepatocyte replication. We show here that low- (1 mg/kg) and high- (10 mg/kg) dose hepatocyte growth factor (HGF) induced replication of 2.1% and 11.1% of hepatocytes in rats, respectively. Lipopolysaccharide (LPS), an inducer of the acute phase response, augmented hepatocyte replication in response to low- and high-dose HGF by 4- and 2-fold, respectively. HGF alone induced moderate levels of c-Jun-N-terminal kinase (JNK) and p44/p42 mitogen-activated protein kinase (MAPK), resulting in moderate levels of AP-1-DNA binding activity. The combination of LPS + HGF increased JNK and AP-1-DNA binding activity more than levels seen with LPS or HGF alone. The activation of Stat3 that was observed after administration of LPS + HGF, but not HGF alone, could contribute to increased transcription of AP-1 components. Because phosphorylation of the c-Jun component of AP-1 by JNK increases its ability to activate transcription, the AP-1 in hepatocytes from animals treated with LPS + HGF may be more active than in rats treated with LPS or HGF alone. LPS may contribute to hepatocyte replication by potentiating the effect of HGF on the activation of both AP-1-DNA binding and transcriptional activity.

Assessings impact of drought on water resources management in the Middle East using the GRACE data and hydrological modeling

NASA Astrophysics Data System (ADS)

Rateb, A., II; Kuo, C. Y.; Imani, M.; Kao, H. C.; Shum, C. K.; Ching, K. E.; Tseng, K. H.; Lan, W. H.; Tseng, T. P.

2017-12-01

The Middle East (ME) region experiences severe freshwater shortages in 90% of the region due primarily to its semi-arid landscape and climate setting, the growth of its population which outpaces world's average population rate by 3.7%, and rapid economic development. The prolonged and intense drought which started in 2007 resulted in the significant decline of surface water availability in the Tigris-Euphrates basin, and exacerbated the anthropogenic groundwater extraction rate, which declined the productivity of agriculture, and displaced hundreds of thousands of people. Therefore, evaluating the impact of the drought on the total water storage (TWS) and groundwater storage (GWS) decline is critical to quantify water availability, towards more effective water resources management in the region. In this study, we use the monthly Gravity Recovery and Climate Experiment (GRACE) twin-satellite mission gravity solutions, covering April 2002 through December 2015, and hydrological models (GLDAS, CLM4.5, and WGHM2.2b) to monitor the TWS and GWS before and after the onset of the pronged drought which started in 2007. We built an effective Slepian basis concentrated over the Arabian Peninsula (AP) and six regions, including Iran, Iraq, North AP, South AP, Syria-Jordan, and Eastern Turkey, to characterize the impact of the drought at the country scale. The results show that the drought has resulted in further reducing the TWS and GWS depletion rate by more than 50%. The ME region experienced a small negative trend between 2002 and 2007, and then the trend dropped dramatically after 2007. The worst affected regions are northern Iraq, northwestern Iran, and North AP. We compared the estimates with agriculture irrigation maps and characterized the depletion rates have been primarily caused by agriculture irrigation, which is directly linked to the pronged drought. Droughts are arguably longer in duration, more frequency and more intense in an increasingly warmer climate. The water-stressed countries in the ME must develop sustainable water resources management plans for the transboundary aquifers, and investigate alternative measures to mitigate the unknown future.

An Increase in the Incidence of Infective Endocarditis in England since 2008: A secular trend interrupted time series analysis

PubMed Central

Dayer, Mark J; Jones, Simon; Prendergast, Bernard; Baddour, Larry M.; Lockhart, Peter B; Thornhill, Martin H

2017-01-01

Background Antibiotic prophylaxis (AP) administered prior to invasive procedures in patients at risk of developing infective endocarditis (IE) has historically been the focus of IE prevention. Recent changes in AP guidelines in the US and Europe have substantially reduced the numbers for whom AP is recommended. In the UK, the National Institute for Health and Care Excellence (NICE) guidelines recommended complete cessation of AP in March 2008. We report the impact of these guidelines on AP prescribing; in addition, IE incidence was examined following the introduction of the guidelines. Methods We analyzed English AP prescribing data from January 2004 to March 2013 and hospital discharge episode statistics for patients with a primary diagnosis of IE from January 2000 to March 2013. Findings AP prescribing rates fell dramatically after introduction of the NICE guidance (10,935 prescriptions/month vs. 2,236 prescriptions/month, p<0·0001). Commencing in March 2008, there was also a significant increase in the number of IE cases/month (0·11 cases/10million/month, CI 0·05–0·16, p<0·0001) above the projected historical trend. By March 2013, there were an additional 35 cases/month than would have been expected if the previous trend had continued. This increase in IE incidence was significant for both ‘high-risk’ and ‘lower-risk’ individuals. Interpretation Although our data do not establish a causal relationship, there has been a substantial reduction in AP prescribing and a significant increase in IE incidence in England since introduction of the NICE guidelines in 2008. Funding Different aspects of this study were supported by Heart Research UK and Simplyhealth [Grant Ref: RG2632/13/14] and NIDCR R03 grant [Ref: 1R03DE023092-01] from the National Institutes for Health. PMID:25467569

Mechanism of action of novel lung edema therapeutic AP301 by activation of the epithelial sodium channel.

PubMed

Shabbir, Waheed; Scherbaum-Hazemi, Parastoo; Tzotzos, Susan; Fischer, Bernhard; Fischer, Hendrik; Pietschmann, Helmut; Lucas, Rudolf; Lemmens-Gruber, Rosa

2013-12-01

AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human tumor necrosis factor lectin-like domain (TIP domain) sequence, is currently being developed as a treatment for lung edema and has been shown to reduce extravascular lung water and improve lung function in mouse, rat, and pig models. The current paradigm for liquid homeostasis in the adult mammalian lung is that passive apical uptake of sodium via the amiloride-sensitive epithelial Na⁺ channel (ENaC) and nonselective cyclic-nucleotide-gated cation channels creates the major driving force for reabsorption of water through the alveolar epithelium in addition to other ion channels such as potassium and chloride channels. AP301 can increase amiloride-sensitive current in A549 cells as well as in freshly isolated type II alveolar epithelial cells from different species. ENaC is expressed endogenously in all of these cell types. Consequently, this study was undertaken to determine whether ENaC is the specific target of AP301. The effect of AP301 in A549 cells as well as in human embryonic kidney cells and Chinese hamster ovary cells heterologously expressing human ENaC subunits (α, β, γ, and δ) was measured in patch clamp experiments. The congener TIP peptide AP318 [Cyclo(4-aminobutanoic acid-GQRETPEGAEAKPWYD)] activated ENaC by increasing single-channel open probability. AP301 increased current in proteolytically activated (cleaved) but not near-silent (uncleaved) ENaC in a reversible manner. αβγ- or δβγ-ENaC coexpression was required for maximal activity. No increase in current was observed after deglycosylation of extracellular domains of ENaC. Thus, our data suggest that the specific interaction of AP301 with both endogenously and heterologously expressed ENaC requires precedent binding to glycosylated extracellular loop(s).

Diadenosine polyphosphates in the tears of aniridia patients.

PubMed

Peral, Assumpta; Carracedo, Gonzalo; Pintor, Jesús

2015-08-01

To quantify diadenosine polyphosphate levels in tears of congenital aniridia patients to estimate the ocular surface changes associated with congenital aniridia compared to normal individuals. Fifteen patients diagnosed with congenital aniridia and a control group of forty volunteers were studied. Tears were collected to quantify the levels of diadenosine polyphosphates Ap4 A and Ap5 A by high-performance liquid chromatography (H.P.L.C). Break-up time (BUT), corneal staining, McMonnies questionnaire and the Schirmer I test were applied to both groups. Dinucleotides in congenital aniridia patients were higher than in control subjects. For the congenital aniridia group, under 15 years old, the values were 0.77 ± 0.01 μm and 0.17 ± 0.02 μm for Ap4 A and Ap5 A, respectively. The group aged from 15 to 40 years old provided concentrations of 4.37 ± 0.97 μm and 0.46 ± 0.05 μm for Ap4 A and Ap5 A, the group over 40 gave concentrations of 11.17 ± 5.53 μm and 0.68 ± 0.17 μm for Ap4 A and Ap5 A. Dinucleotide concentrations increased with age, being statistically significant different among the three age groups (p < 0.05). Congenital aniridia patients showed a normal tear secretion and no dry eye McMonnies scores, except for the group over 40 years old. BUT values decreased and corneal staining increased with age and correlated with the levels of diadenosine polyphosphates (p < 0.05). The levels of dinucleotides in tears increase in aniridia patients compared with healthy subjects, and they seem to be related with the progression of corneal disorders in aniridia patients, both of which increase with ageing. © 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Treatment with pentylenetetrazole (PTZ) and 4-aminopyridine (4-AP) differently affects survival, locomotor activity, and biochemical markers in Drosophila melanogaster.

PubMed

Soares, Deividi C S; Portela, José L R; Roos, Daniel H; Rodrigues, Nathane R; Gomes, Karen K; Macedo, Giulianna E; Posser, Thais; Franco, Jeferson L; Hassan, Waseem; Puntel, Robson L

2018-05-01

PTZ is a convulsive agent that acts via selective blockage of GABA A receptor channels, whereas 4-AP leads to a convulsive episode via blockage of K + channels. However, the mechanism(s) by which pentylenetetrazole (PTZ) and 4-aminopyridine (4-AP) cause toxicity to Drosophila melanogaster needs to be properly explored, once it will help in establishing an alternative model for development of proper therapeutic strategies and also to counteract the changes associated with exposure to both epileptic drugs. For the purpose, we investigated the effects of exposure (48 h) to PTZ (60 mM) and/or 4-AP (20 mM) on survival, locomotor performance, and biochemical markers in the body and/or head of flies. 4-AP-fed flies presented a higher incidence of mortality and a worse performance in the open field test as compared to non-treated flies. 4-AP also caused a significant increase in the reactive species (RS) and protein carbonyl (PC) content in the body and head. Also a significant increase in catalase and acetylcholinesterase (AChE) activities was observed in the body. In the same vein, PTZ exposure resulted in a significant increase in RS, thiobarbituric acid reactive substances (TBARS), PC content, and catalase activity in the body. PTZ exposure also caused a significant increase in AChE activity both in body and head. It is important to note that PTZ-treated flies also down-regulated the NRF 2 expression. Moreover, both 4AP- and PTZ-fed flies presented a significant decrease in MTT reduction, down-regulation, and inhibition of SOD in body. However, SOD was significantly more active in the head of both 4-AP and PTZ-treated flies. Our findings provide evidence regarding the toxicological potential of both PTZ and/or 4-AP to flies. This model will help in decoding the underlying toxicological mechanisms of the stated drugs. It will also help to properly investigate the therapeutic strategies and to counteract the drastic changes associated with both epileptogenic drugs.

Bio-oil based biorefinery strategy for the production of succinic acid.

PubMed

Wang, Caixia; Thygesen, Anders; Liu, Yilan; Li, Qiang; Yang, Maohua; Dang, Dan; Wang, Ze; Wan, Yinhua; Lin, Weigang; Xing, Jianmin

2013-01-01

Succinic acid is one of the key platform chemicals which can be produced via biotechnology process instead of petrochemical process. Biomass derived bio-oil have been investigated intensively as an alternative of diesel and gasoline fuels. Bio-oil could be fractionized into organic phase and aqueous phase parts. The organic phase bio-oil can be easily upgraded to transport fuel. The aqueous phase bio-oil (AP-bio-oil) is of low value. There is no report for its usage or upgrading via biological methods. In this paper, the use of AP-bio-oil for the production of succinic acid was investigated. The transgenic E. coli strain could grow in modified M9 medium containing 20 v/v% AP-bio-oil with an increase in OD from 0.25 to 1.09. And 0.38 g/L succinic acid was produced. With the presence of 4 g/L glucose in the medium, succinic acid concentration increased from 1.4 to 2.4 g/L by addition of 20 v/v% AP-bio-oil. When enzymatic hydrolysate of corn stover was used as carbon source, 10.3 g/L succinic acid was produced. The obtained succinic acid concentration increased to 11.5 g/L when 12.5 v/v% AP-bio-oil was added. However, it decreased to 8 g/L when 50 v/v% AP-bio-oil was added. GC-MS analysis revealed that some low molecular carbon compounds in the AP-bio-oil were utilized by E. coli. The results indicate that AP-bio-oil can be used by E. coli for cell growth and succinic acid production.

Bio-oil based biorefinery strategy for the production of succinic acid

PubMed Central

2013-01-01

Background Succinic acid is one of the key platform chemicals which can be produced via biotechnology process instead of petrochemical process. Biomass derived bio-oil have been investigated intensively as an alternative of diesel and gasoline fuels. Bio-oil could be fractionized into organic phase and aqueous phase parts. The organic phase bio-oil can be easily upgraded to transport fuel. The aqueous phase bio-oil (AP-bio-oil) is of low value. There is no report for its usage or upgrading via biological methods. In this paper, the use of AP-bio-oil for the production of succinic acid was investigated. Results The transgenic E. coli strain could grow in modified M9 medium containing 20 v/v% AP-bio-oil with an increase in OD from 0.25 to 1.09. And 0.38 g/L succinic acid was produced. With the presence of 4 g/L glucose in the medium, succinic acid concentration increased from 1.4 to 2.4 g/L by addition of 20 v/v% AP-bio-oil. When enzymatic hydrolysate of corn stover was used as carbon source, 10.3 g/L succinic acid was produced. The obtained succinic acid concentration increased to 11.5 g/L when 12.5 v/v% AP-bio-oil was added. However, it decreased to 8 g/L when 50 v/v% AP-bio-oil was added. GC-MS analysis revealed that some low molecular carbon compounds in the AP-bio-oil were utilized by E. coli. Conclusions The results indicate that AP-bio-oil can be used by E. coli for cell growth and succinic acid production. PMID:23657107

Human bone marrow-derived clonal mesenchymal stem cells inhibit inflammation and reduce acute pancreatitis in rats.

PubMed

Jung, Kyung Hee; Song, Sun U; Yi, Tacghee; Jeon, Myung-Shin; Hong, Sang-Won; Zheng, Hong-Mei; Lee, Hee-Seung; Choi, Myung-Joo; Lee, Don-Haeng; Hong, Soon-Sun

2011-03-01

Acute pancreatitis (AP) has a high mortality rate; repetitive AP induces chronic AP and pancreatic adenocarcinoma. Mesenchymal stem cells (MSCs) have immunoregulatory effects and reduce inflammation. We developed a protocol to isolate human bone marrow-derived clonal MSCs (hcMSCs) from bone marrow aspirate and investigated the effects of these cells in rat models of mild and severe AP. Mild AP was induced in Sprague-Dawley rats by 3 intraperitoneal injections of cerulein (100 μg/kg), given at 2-hour intervals; severe AP was induced by intraparenchymal injection of 3% sodium taurocholate solution. hcMSCs were labeled with CM-1,1'-dioctadecyl-3,3,3'-tetramethylindo-carbocyanine perchloride and administered to rats through the tail vein. hcMSCs underwent self-renewal and had multipotent differentiation capacities and immunoregulatory functions. Greater numbers of infused hcMSCs were detected in pancreas of rats with mild and severe AP than of control rats. Infused hcMSCs reduced acinar-cell degeneration, pancreatic edema, and inflammatory cell infiltration in each model of pancreatitis. The hcMSCs reduced expression of inflammation mediators and cytokines in rats with mild and severe AP. hcMSCs suppressed the mixed lymphocyte reaction and increased expression of Foxp3(+) (a marker of regulatory T cells) in cultured rat lymph node cells. Rats with mild or severe AP that were given infusions of hcMSCs had reduced numbers of CD3(+) T cells and increased expression of Foxp3(+) in pancreas tissues. hcMSCs reduced inflammation and damage to pancreatic tissue in a rat model of AP; they reduced levels of cytokines and induced numbers of Foxp3(+) regulatory T cells. hcMSCs might be developed as a cell therapy for pancreatitis. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Amelioration of CCl4-induced liver injury in rats by selenizing Astragalus polysaccharides: Role of proinflammatory cytokines, oxidative stress and hepatic stellate cells.

PubMed

Hamid, Mohammed; Liu, Dandan; Abdulrahim, Yassin; Liu, Yunhuan; Qian, Gang; Khan, Alamzeb; Gan, Fang; Huang, Kehe

2017-10-01

Selenizing Astragalus polysaccharides (sAPS) were prepared by nitric acid-sodium selenite method. Effect of sAPS on carbon tetrachloride (CCl4)-induced liver injury and the underlying mechanisms were investigated in the rat. Forty male Wistar rats were divided into five equal groups as follows: control group; CCl 4 group; CCl 4 +Astragalus polysaccharides group; CCl 4 +sodium selenite group and CCl 4 +selenizing Astragalus polysaccharides group. The results showed that sAPS significantly decreased the levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase in the serum, malondialdehyde and hydroxyproline content in liver (P<0.01), and increased the levels of total protein, total antioxidant capacity, glutathione peroxidase, and superoxide dismutase in liver of rats induced by CCl 4. In addition, expression levels of antioxidant-related genes (GPX1, SOD1, and Nrf2) were significantly increased following supplementation of the sAPS (P<0.01). Furthermore, sAPS effectively ameliorated CCl 4 induced hepatic necrosis and inflammation, and it also reduced the expression levels of proinflammatory cytokines including TNF-α, IL-6, COX-2 and NFκB (P<0.01) . Moreover, sAPS significantly decreased the expression levels of α-smooth muscle actin, collagen 1, TGF-β1, but increased the Bcl-2/Bax mRNA ratio in rats administered CCl 4 (P<0.01). Taken together, it could be concluded that sAPS could increase the activities of Astragalus polysaccharides and sodium selenite to protect the liver from damage by attenuating hepatic inflammation, oxidative stress, fibrogenesis, and induces apoptosis and cell cycle arrest in hepatic stellate cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

Geraniol blocks calcium and potassium channels in the mammalian myocardium: useful effects to treat arrhythmias.

PubMed

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).

Ketamine versus alfentanil combined with propofol for sedation in colonoscopy procedures: a randomized prospective study.

PubMed

Türk, Hacer Şebnem; Aydoğmuş, Meltem; Ünsal, Oya; Işıl, Canan Tülay; Citgez, Bülent; Oba, Sibel; Açık, Mehmet Eren

2014-12-01

Different drug combinations are used for sedation in colonoscopy procedures. A ketamine-propofol (ketofol) mixture provides effective sedation and has minimal adverse effects. Alfentanil also provides anesthesia for short surgical procedures by incremental injection as an adjunct. However, no study has investigated the use of ketofol compared with an opioid-propofol combination in colonoscopic procedures. A total of 70 patients, ASA physical status I-II, scheduled to undergo elective colonoscopy, were enrolled in this prospective randomized study and allocated to two groups. After premedication, sedation induction was performed with 0.5 mg/kg ketamine +1 mg/kg propofol in Group KP, and 10 mg/kg alfentanil +1 mg/kg propofol in Group AP. Propofol was added when required. Demographic data, colonoscopy duration, recovery time, discharge time, mean arterial pressure (MAP), heart rate (HR), peripheral oxygen saturation, Ramsey Sedation Scale values, colonoscopy patients' satisfaction scores, and complications were recorded. The need for additional propofol doses was significantly higher in Group AP than in Group KP. MAP at minute 1 and 5, Ramsey Sedation Scale at minute 5, and discharge time were significantly higher in Group KP than in Group AP. Additional propofol doses and total propofol dose were significantly lower in Group KP than in Group AP. Ketofol provided better hemodynamic stability and quality of sedation compared with alfentanil-propofol combination in elective colonoscopy, and required fewer additional propofol; however, it prolonged discharge time. Both combinations can safely be used in colonoscopy sedation.

Electrophysiological characteristics of IB4-negative TRPV1-expressing muscle afferent DRG neurons.

PubMed

Lin, Yi-Wen; Chen, Chih-Cheng

2015-01-01

Muscle afferent neurons that express transient receptor potential vanilloid type I (TRPV1) are responsible for muscle pain associated with tissue acidosis. We have previously found that TRPV1 of isolectin B4 (IB4)-negative muscle nociceptors plays an important role in the acid-induced hyperalgesic priming and the development of chronic hyperalgesia in a mouse model of fibromyalgia. To understand the electrophysiological properties of the TRPV1-expressing muscle afferent neurons, we used whole-cell patch clamp recording to study the acid responsiveness and action potential (AP) configuration of capsaicin-sensitive neurons innervating to gastrocnemius muscle. Here we showed that IB4-negative TRPV1-expressing muscle afferent neurons are heterogeneous in terms of cell size, resting membrane potential, AP configuration, tetrodotoxin (TTX)-resistance, and acid-induced current (I acid), as well as capsaicin-induced current (I cap). TRPV1-expressing neurons were all acid-sensitive and could be divided into two acid-sensitive groups depending on an acid-induced sustained current (type I) or an acid-induced biphasic ASIC3-like current (type II). Type I TRPV1-expressing neurons were distinguishable from type II TRPV1-expressing neurons in AP overshoot, after-hyperpolarization duration, and all I acid parameters, but not in AP threshold, TTX-resistance, resting membrane potential, and I cap parameters. These differential biophysical properties of TRPV1-expressing neurons might partially annotate their different roles involved in the development and maintenance of chronic muscle pain.

A Fiber-Based Ratiometric Optical Cardiac Mapping Channel Using a Diffraction Grating and Split Detector

PubMed Central

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

The Na+/K+ pump is an important modulator of refractoriness and rotor dynamics in human atrial tissue.

PubMed

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.

Does short-term application of an Ilizarov frame with transfixion pins correct relapsed clubfoot in children?

PubMed

Refai, Mohamed Ahmed; Song, Sang-Heon; Song, Hae-Ryong

2012-07-01

Treatment of relapsed clubfoot after soft tissue release in children is difficult because of the high recurrence rate and related complications. Even though the Ilizarov method is used for soft tissue distraction, there is a high incidence of recurrence after removal of the Ilizarov frame owing to previous contracture of soft tissue and a skin scar. We asked (1) whether transfixation of midfoot joints by temporary K wires during the consolidation stage after short-term application of an Ilizarov frame would maintain correction of the relapsed clubfoot clinicoradiologically and (2) whether this method would reduce the rate of recurrence and related complications in patients with a skin scar from previous surgery. We retrospectively reviewed 18 patients (19 feet) with relapsed clubfeet who underwent correction by soft tissue distraction using an Ilizarov ring fixator, between March 2005 and June 2008. The mean age of the patients was 8 ± 2 years (range, 4-15 years). K wire fixation for the midfoot joints combined with a below-knee cast were used during the consolidation stage. The minimum followup was 2 years (mean, 4.5 years; range, 2-6 years). The average duration of frame application was 5 weeks; the mean duration of treatment was 11 weeks. At last followup, 16 of 19 feet were painless and plantigrade and only three of 19 feet had recurrence. The mean preoperative clinical American Foot and Ankle Society (AOFAS) score had increased at last followup (57 versus 81). The values of the AP talocalcaneal, AP talo-first metatarsal, and lateral calcaneo-first metatarsal angles improved after treatment. The three recurrent clubfeet were treated by corrective osteotomies and Ilizarov frame application. This method could maintain the correction of relapsed clubfoot in children and reduce the recurrence rate and complications regardless of the presence of a skin scar owing to previous surgery.

Transmural Heterogeneity and Remodeling of Ventricular Excitation-Contraction Coupling in Human Heart Failure

PubMed Central

Lou, Qing; Fedorov, Vadim V.; Glukhov, Alexey V.; Moazami, Nader; Fast, Vladimir G.; Efimov, Igor R.

2011-01-01

Background Excitation-contraction (EC) coupling is altered in the end-stage heart failure (HF). However, spatial heterogeneity of this remodeling has not been established at the tissue level in failing human heart. The objective is to study functional remodeling of EC coupling and calcium handling in failing and nonfailing human hearts. Methods and Results We simultaneously optically mapped action potentials (AP) and calcium transients (CaT) in coronary-perfused left ventricular wedge preparations from nonfailing (n = 6) and failing (n = 5) human hearts. Our major findings are: (1) CaT duration minus AP duration was longer at sub-endocardium in failing compared to nonfailing hearts during bradycardia (40 beats/min). (2) The transmural gradient of CaT duration was significantly smaller in failing hearts compared with nonfailing hearts at fast pacing rates (100 beats/min). (3) CaT in failing hearts had a flattened plateau at the midmyocardium; and exhibited a “two-component” slow rise at sub-endocardium in three failing hearts. (4) CaT relaxation was slower at sub-endocardium than that at sub-epicardium in both groups. Protein expression of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) was lower at sub-endocardium than that at sub-epicardium in both nonfailing and failing hearts. SERCA2a protein expression at sub-endocardium was lower in hearts with ischemic cardiomyopathy compared with nonischemic cardiomyopathy. Conclusions For the first time, we present direct experimental evidence of transmural heterogeneity of EC coupling and calcium handling in human hearts. End-stage HF is associated with the heterogeneous remodeling of EC coupling and calcium handling. PMID:21502574

High diadenosine tetraphosphate (Ap4A) level in germ cells and embryos of sea urchin and Xenopus and its effect on DNA synthesis.

PubMed

Weinmann-Dorsch, C; Grummt, F

1985-09-01

Ap4A levels in sperms, eggs and different developmental stages of sea urchin (Psammechinus miliaris) and (Xenopus laevis) were determined by a method based on ATP measurement with luciferin/luciferase after splitting diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) into ATP and AMP. Appreciable storage pools of Ap4A were found in unfertilized eggs of Psammechinus and Xenopus as well as in sea urchin sperms. The actual Ap4A concentration of 28 microM in sperm represents the highest Ap4A level so far observed in eukaryotic cells. Upon fertilization an instant onset of de novo synthesis of Ap4A was demonstrated. Ap4A levels during early embryogenesis of P. miliaris and X. laevis (2.5-4 microM) are higher than those in exponentially growing mammalian culture cells and mammalian fetuses. Microinjection of Ap4A into unfertilized eggs of Psammechinus miliaris caused a 3-7 fold increase of DNA synthesis in comparison with mock-injected eggs.

Auditory processing in absolute pitch possessors

NASA Astrophysics Data System (ADS)

McKetton, Larissa; Schneider, Keith A.

2018-05-01

Absolute pitch (AP) is a rare ability in classifying a musical pitch without a reference standard. It has been of great interest to researchers studying auditory processing and music cognition since it is seldom expressed and sheds light on influences pertaining to neurodevelopmental biological predispositions and the onset of musical training. We investigated the smallest frequency that could be detected or just noticeable difference (JND) between two pitches. Here, we report significant differences in JND thresholds in AP musicians and non-AP musicians compared to non-musician control groups at both 1000 Hz and 987.76 Hz testing frequencies. Although the AP-musicians did better than non-AP musicians, the difference was not significant. In addition, we looked at neuro-anatomical correlates of musicianship and AP using structural MRI. We report increased cortical thickness of the left Heschl's Gyrus (HG) and decreased cortical thickness of the inferior frontal opercular gyrus (IFO) and circular insular sulcus volume (CIS) in AP compared to non-AP musicians and controls. These structures may therefore be optimally enhanced and reduced to form the most efficient network for AP to emerge.

INTERSESSION RELIABILITY OF UPPER EXTREMITY ISOKINETIC PUSH-PULL TESTING.

PubMed

Riemann, Bryan L; Davis, Sarah E; Huet, Kevin; Davies, George J

2016-02-01

Based on the frequency pushing and pulling patterns are used in functional activities, there is a need to establish an objective method of quantifying the muscle performance characteristics associated with these motions, particularly during the later stages of rehabilitation as criteria for discharge. While isokinetic assessment offers an approach to quantifying muscle performance, little is known about closed kinetic chain (CKC) isokinetic testing of the upper extremity (UE). To determine the intersession reliability of isokinetic upper extremity measurement of pushing and pulling peak force and average power at slow (0.24 m/s), medium (0.43 m/s) and fast (0.61 m/s) velocities in healthy young adults. The secondary purpose was to compare pushing and pulling peak force (PF) and average power (AP) between the upper extremity limbs (dominant, non-dominant) across the three velocities. Twenty-four physically active men and women completed a test-retest (>96 hours) protocol in order to establish isokinetic UE CKC reliability of PF and AP during five maximal push and pull repetitions at three velocities. Both limb and speed orders were randomized between subjects. High test-retest relative reliability using intraclass correlation coefficients (ICC2, 1) were revealed for PF (.91-.97) and AP (.85-.95) across velocities, limbs and directions. PF typical error (% coefficient of variation) ranged from 6.1% to 11.3% while AP ranged from 9.9% to 26.7%. PF decreased significantly (p < .05) as velocity increased whereas AP increased as velocity increased. PF and AP during pushing were significantly greater than pulling at all velocities, however the push-pull differences in PF became less as velocity increased. There were no significant differences identified between the dominant and nondominant limbs. Isokinetically derived UE CKC push-pull PF and AP are reliable measures. The lack of limb differences in healthy normal participants suggests that clinicians can consider bilateral comparisons when interpreting test performance. The increase in pushing PF and AP compared to pulling can be attributed to the muscles involved and the frequency that pushing patterns are used during functional activities. 3.

Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations.

PubMed

Huybrechts, Krista F; Hernández-Díaz, Sonia; Patorno, Elisabetta; Desai, Rishi J; Mogun, Helen; Dejene, Sara Z; Cohen, Jacqueline M; Panchaud, Alice; Cohen, Lee; Bateman, Brian T

2016-09-01

The frequency of antipsychotic (AP) use during pregnancy has approximately doubled during the last decade. However, little is known about their safety for the developing fetus, and concerns have been raised about a potential association with congenital malformations. To examine the risk for congenital malformations overall and cardiac malformations associated with first-trimester exposure to APs. This nationwide sample of 1 360 101 pregnant women enrolled in Medicaid with a live-born infant constituted the pregnancy cohort nested in the Medicaid Analytic Extract database, which included data from January 1, 2000, to December 31, 2010. Participants were enrolled in Medicaid from 3 months before their last menstrual period through at least 1 month after delivery. Relative risks (RRs) were estimated using generalized linear models with fine stratification on the propensity score to control for the underlying psychiatric disorders and other potential confounders. Data were analyzed during 2015. Use of APs during the first trimester, the etiologically relevant period for organogenesis. Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery. Of the 1 341 715 pregnancies that met inclusion criteria (mean [SD] age of women, 24.02 [5.77] years), 9258 (0.69%) filled at least 1 prescription for an atypical AP and 733 (0.05%) filled at least 1 prescription for a typical AP during the first trimester. Overall, 32.7 (95% CI, 32.4-33.0) per 1000 births not exposed to APs were diagnosed with congenital malformations compared with 44.5 (95% CI, 40.5-48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6-54.7) per 1000 births exposed to typical APs. Unadjusted analyses suggested an increased risk for malformations overall for atypical APs (RR, 1.36; 95% CI, 1.24-1.50) but not for typical APs (RR, 1.17; 95% CI, 0.81-1.68). After confounding adjustment, the RR was reduced to 1.05 (95% CI, 0.96-1.16) for atypical APs and 0.90 (95% CI, 0.62-1.31) for typical APs. The findings for cardiac malformations were similar. For the individual agents examined, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02-1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88-1.81) was found for risperidone that was independent of measured confounders. Evidence from this large study suggests that use of APs early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.

Diadenosine polyphosphates (Ap3A and Ap4A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana.

PubMed

Pietrowska-Borek, Małgorzata; Nuc, Katarzyna; Zielezińska, Małgorzata; Guranowski, Andrzej

2011-12-01

It is known that cells under stress accumulate various dinucleoside polyphosphates, compounds suggested to function as alarmones. In plants, the phenylpropanoid pathways yield metabolites protecting these organisms against various types of stress. Observations reported in this communication link these two phenomena and provide an example of a metabolic "addressee" for an "alarm" signaled by diadenosine triphosphate (Ap3A) or diadenosine tetraphosphate (Ap4A). In response to added Ap3A or Ap4A, seedlings of Arabidopsis thaliana incubated in full nutrition medium increased both the expression of the genes for and the specific activity of phenylalanine ammonia-lyase and 4-coumarate:coenzyme A ligase, enzymes that control the beginning of the phenylpropanoid pathway. Neither adenine mononucleotides (AMP, ADP or ATP) nor adenosine evoked such effects. Reactions catalyzed in vitro by these enzymes were not affected by Ap3A or Ap4A.

MRP2 mediated drug-drug interaction: indomethacin increases sulfasalazine absorption in the small intestine, potentially decreasing its colonic targeting.

PubMed

Dahan, Arik; Amidon, Gordon L

2010-02-15

We have recently shown that efflux transport, mediated by multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP), is responsible for sulfasalazine low-permeability in the small intestine, thereby enabling its colonic targeting and therapeutic action. The purpose of the present study was to evaluate the potential pharmacokinetic interaction between indomethacin and sulfasalazine, in the mechanism of efflux transporter competition. The concentration-dependent effects of indomethacin on sulfasalazine intestinal epithelial transport were investigated across Caco-2 cell monolayers, in both apical to basolateral (AP-BL) and BL-AP directions. The interaction was then investigated in the in situ single-pass rat jejunal perfusion model. Sulfasalazine displayed 30-fold higher BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion. Indomethacin significantly increased AP-BL and decreased BL-AP sulfasalazine Caco-2 transport, in a concentration-dependent manner, with IC(50) values of 75 and 196 microM respectively. In the rat model, higher sulfasalazine concentrations resulted in higher intestinal permeability, consistent with saturation of efflux transporter. Without indomethacin, sulfasalazine demonstrated low rat jejunal permeability (vs. metoprolol). Indomethacin significantly increased sulfasalazine P(eff), effectively shifting it from BCS (biopharmaceutics classification system) Class IV to II. In conclusion, the data indicate that concomitant intake of indomethacin and sulfasalazine may lead to increased absorption of sulfasalazine in the small intestine, thereby reducing its colonic concentration and potentially altering its therapeutic effect. Copyright 2009 Elsevier B.V. All rights reserved.

Amorphous silicon photovoltaic manufacturing technology, phase 2A

NASA Astrophysics Data System (ADS)

Duran, G.; Mackamul, K.; Metcalf, D.

1995-01-01

Utility Power Group (UPG), and its lower-tier subcontractor, Advanced Photovoltaic Systems, Inc. (APS) have conducted efforts in developing their manufacturing lines. UPG has focused on the automation of encapsulation and termination processes developed in Phase 1. APS has focused on completion of the encapsulation and module design tasks, while continuing the process and quality control and automation projects. The goal is to produce 55 watt (stabilized) EP50 modules in a new facility. In the APS Trenton EUREKA manufacturing facility, APS has: (1) Developed high throughput lamination procedures; (2) Optimized existing module designs; (3) Developed new module designs for architectural applications; (4) Developed enhanced deposition parameter control; (5) Designed equipment required to manufacture new EUREKA modules developed during Phase II; (6) Improved uniformity of thin-film materials deposition; and (7) Improved the stabilized power output of the APS EP50 EUREKA module to 55 watts. In the APS Fairfield EUREKA manufacturing facility, APS has: (1) Introduced the new products developed under Phase 1 into the APS Fairfield EUREKA module production line; (2) Increased the extent of automation in the production line; (3) Introduced Statistical Process Control to the module production line; and (4) Transferred-progress made in the APS Trenton facility into the APS Fairfield facility.

[Pancreas and biliary tract: recent developments].

PubMed

de-Madaria, Enrique

2014-09-01

Acute pancreatitis (AP) is a common disease that is associated with significant morbidity and considerable mortality. In this article, developments relating to this disease that were presented in DDW 2014 are reviewed. Pancreatic steatosis could be a cause of recurrent AP. Patients with DM have an increased incidence of AP and pancreatic cancer. The use of anti-TNF drugs in inflammatory bowel disease may protect against the occurrence of AP. The presence of pancreas divisum protects against acute biliary pancreatitis. The PANCODE system for describing local complications of AP has good interobserver agreement, when the new definitions of the revised Atlanta classification are applied. The use of prophylactic antibiotics in early-stage AP predisposes the development of intra-abdominal fungal infections. Fluid sequestration in AP is linked with young age, alcoholism and indicators of systemic inflammatory response syndrome. The most common cause of mortality in AP is early onset of multiple organ failure, not pancreatic necrosis infection. Patients with AP and vitamin D deficiency could benefit from taking vitamin D supplements. Moderate fluid administration in emergencies (500-1000 mL) could be associated with better AP development. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Anti-Hypertensive Effects of Acacia Polyphenol in Spontaneously Hypertensive Rats

PubMed Central

Ikarashi, Nobutomo; Toda, Takahiro; Hatakeyama, Yusuke; Kusunoki, Yoshiki; Kon, Risako; Mizukami, Nanaho; Kaneko, Miho; Ogawa, Sosuke; Sugiyama, Kiyoshi

2018-01-01

We have previously demonstrated that acacia polyphenol (AP) exerts strong anti-obesity, anti-diabetic, and anti-atopic dermatitis effects. In the present study, we investigated the anti-hypertensive effects of AP. Spontaneously hypertensive rats (SHR) with hypertension and control Wistar Kyoto rats (WKY) were used. WKY and SHR were fed AP-containing food or AP-free food (control group) ad libitum for 4 weeks, and their blood pressures were measured. After AP administration, both systolic and diastolic blood pressures were significantly lower in the SHR group than in the control group. There were no differences in the systolic or diastolic blood pressure of WKY between the AP group and the control group. Angiotensin-converting enzyme (ACE) activity, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression, and superoxide dismutase (SOD) activity in SHR kidneys were not altered by AP administration. Blood SOD activity in SHR was significantly higher in the AP group than in the control group. AP exerts anti-hypertensive effects on hypertension but has almost no effect on normal blood pressure. The anti-hypertensive effects of AP may be related to the anti-oxidative effects of increased blood SOD activity. PMID:29494506

Electroconvulsive Therapy for Agitation in Schizophrenia: Metaanalysis of Randomized Controlled Trials.

PubMed

Gu, Xiaojing; Zheng, Wei; Guo, Tong; Ungvari, Gabor S; Chiu, Helen F K; Cao, Xiaolan; D'Arcy, Carl; Meng, Xiangfei; Ning, Yuping; Xiang, Yutao

2017-02-25

Agitation poses a significant challenge in the treatment of schizophrenia. Electroconvulsive therapy (ECT) is a fast, effective and safe treatment for a variety of psychiatric disorders, but no meta-analysis of ECT treatment for agitation in schizophrenia has yet been reported. To systematically evaluate the efficacy and safety of ECT alone or ECT-antipsychotics (APs) combination for agitation in schizophrenia. Systematic literature search of randomized controlled trials (RCTs) was performed. Two independent evaluators selected studies, extracted data about outcomes and safety with available data, conducted quality assessment and data synthesis. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to judge the level of the overall evidence of main outcomes. Seven RCTs from China, including ECT alone (4 RCTs with 5 treatment arms, n=240) and ECT-APs combination (3 RCTs, n=240), were identified. Participants in the studies were on average 34.3(4.5) years of age and lasted an average of 4.3(3.1) weeks of treatment duration. All 7 RCTs were non-blinded, and were rated as low quality based on Jadad scale. Meta-analysis of the pooled sample found no significant difference in the improvement of the agitation sub-score of the Positive and Negative Syndrome Scale (PANSS) when ECT alone (weighted mean difference=-0.90, (95% confidence interval (CI): -2.91, 1.11), p=0.38) or ECT-APs combination (WMD=-1.34, (95%CI: -4.07, 1.39), p=0.33) compared with APs monotherapy. However, ECT alone was superior to APs monotherapy regarding PANSS total score (WMD=-7.13, I 2 =0%, p =0.004) and its excitement sub-score (WMD=-1.97, p <0.0001) as well as the PANSS total score at 14 days (WMD=-7.13, I 2 =0%, p =0.004) and its excitement sub-score at 7 and 14 days (WMD=-1.97 to -1.92, p =0.002 to 0.0001) after ECT. The ECT-APs combination was superior to APs monotherapy with respect to the PANSS total score at treatment endpoint (WMD=-10.40, p=0.03) and 7 days (WMD=-5.01, p =0.02). Headache (number-needed-to-harm (NNH)=3, 95%CI=2-4) was more frequent in the ECT alone group compared to AP monotherapy. According to the GRADE approach, the evidence levels of main outcomes were rated as ''very low'' (37.5%) and "low" (50%). Pooling of the data based on 7 RCTs from China found no advantage of ECT alone or ECT-APs combination in the treatment of agitation related outcomes in schizophrenia patients. However, ECT alone or ECT-APs combination were associated with significant reduction in the PANSS total score. High-quality RCTs are needed to confirm the current interpretations.

Pathogenic lysosomal depletion in Parkinson's disease.

PubMed

Dehay, Benjamin; Bové, Jordi; Rodríguez-Muela, Natalia; Perier, Celine; Recasens, Ariadna; Boya, Patricia; Vila, Miquel

2010-09-15

Mounting evidence suggests a role for autophagy dysregulation in Parkinson's disease (PD). The bulk degradation of cytoplasmic proteins (including α-synuclein) and organelles (such as mitochondria) is mediated by macroautophagy, which involves the sequestration of cytosolic components into autophagosomes (AP) and its delivery to lysosomes. Accumulation of AP occurs in postmortem brain samples from PD patients, which has been widely attributed to an induction of autophagy. However, the cause and pathogenic significance of these changes remain unknown. Here we found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD that AP accumulation and dopaminergic cell death are preceded by a marked decrease in the amount of lysosomes within dopaminergic neurons. Lysosomal depletion was secondary to the abnormal permeabilization of lysosomal membranes induced by increased mitochondrial-derived reactive oxygen species. Lysosomal permeabilization resulted in a defective clearance and subsequent accumulation of undegraded AP and contributed directly to neurodegeneration by the ectopic release of lysosomal proteases into the cytosol. Lysosomal breakdown and AP accumulation also occurred in PD brain samples, where Lewy bodies were strongly immunoreactive for AP markers. Induction of lysosomal biogenesis by genetic or pharmacological activation of lysosomal transcription factor EB restored lysosomal levels, increased AP clearance and attenuated 1-methyl-4-phenylpyridinium-induced cell death. Similarly, the autophagy-enhancer compound rapamycin attenuated PD-related dopaminergic neurodegeneration, both in vitro and in vivo, by restoring lysosomal levels. Our results indicate that AP accumulation in PD results from defective lysosomal-mediated AP clearance secondary to lysosomal depletion. Restoration of lysosomal levels and function may thus represent a novel neuroprotective strategy in PD.

Fractional diffusion models of cardiac electrical propagation: role of structural heterogeneity in dispersion of repolarization

PubMed Central

Bueno-Orovio, Alfonso; Kay, David; Grau, Vicente; Rodriguez, Blanca; Burrage, Kevin

2014-01-01

Impulse propagation in biological tissues is known to be modulated by structural heterogeneity. In cardiac muscle, improved understanding on how this heterogeneity influences electrical spread is key to advancing our interpretation of dispersion of repolarization. We propose fractional diffusion models as a novel mathematical description of structurally heterogeneous excitable media, as a means of representing the modulation of the total electric field by the secondary electrical sources associated with tissue inhomogeneities. Our results, analysed against in vivo human recordings and experimental data of different animal species, indicate that structural heterogeneity underlies relevant characteristics of cardiac electrical propagation at tissue level. These include conduction effects on action potential (AP) morphology, the shortening of AP duration along the activation pathway and the progressive modulation by premature beats of spatial patterns of dispersion of repolarization. The proposed approach may also have important implications in other research fields involving excitable complex media. PMID:24920109

ASRM propellant and igniter propellant development and process scale-up

NASA Technical Reports Server (NTRS)

Landers, L. C.; Booth, D. W.; Stanley, C. B.; Ricks, D. W.

1993-01-01

A program of formulation and process development for ANB-3652 motor propellant was conducted to validate design concepts and screen critical propellant composition and process parameters. Design experiments resulted in the selection of a less active grade of ferric oxide to provide better burning rate control, the establishment of AP fluidization conditions that minimized the adverse effects of particle attrition, and the selection of a higher mix temperature to improve mechanical properties. It is shown that the propellant can be formulated with AP and aluminum powder from various producers. An extended duration pilot plant run demonstrated stable equipment operation and excellent reproducibility of propellant properties. A similar program of formulation and process optimization culminating in large batch scaleup was conducted for ANB-3672 igniter propellant. The results for both ANB-3652 and ANB 37672 confirmed that their processing characteristics are compatible with full-scale production.

AP214, an analogue of α-melanocyte-stimulating hormone, ameliorates sepsis-induced acute kidney injury and mortality

PubMed Central

Doi, Kent; Hu, Xuzhen; Yuen, Peter S.T.; Leelahavanichkul, Asada; Yasuda, Hideo; Kim, Soo Mi; Schnermann, Jürgen; Jonassen, Thomas E.N.; Frøkiær, Jørgen; Nielsen, Søren; Star, Robert A.

2008-01-01

Sepsis remains a serious problem in critically ill patients with the mortality increasing to over half when there is attendant acute kidney injury. α-Melanocyte-stimulating hormone is a potent anti-inflammatory cytokine that inhibits many forms of inflammation including that with acute kidney injury. We tested whether a new α-melanocyte-stimulating hormone analogue (AP214), which has increased binding affinity to melanocortin receptors, improves sepsis-induced kidney injury and mortality using a cecal ligation and puncture mouse model. In the lethal cecal ligation-puncture model of sepsis, severe hypotension and bradycardia resulted and AP214 attenuated acute kidney injury of the lethal model with a bell-shaped dose-response curve. An optimum AP214 dose reduced acute kidney injury even when it was administered 6 hr after surgery and it significantly improved blood pressure and heart rate. AP214 reduced serum TNF-α and IL-10 levels with a bell-shaped dose-response curve. Additionally; NF-κB activation in the kidney and spleen, and splenocyte apoptosis were decreased by the treatment. AP214 significantly improved survival in both lethal and sublethal models. We have shown that AP214 improves hemodynamic failure, acute kidney injury, mortality and splenocyte apoptosis attenuating pro- and anti-inflammatory actions due to sepsis. PMID:18354376

Molecular and biochemical characterisation of two aspartic proteinases TcAP1 and TcAP2 from Theobroma cacao seeds.

PubMed

Laloi, Maryse; McCarthy, James; Morandi, Olivia; Gysler, Christof; Bucheli, Peter

2002-09-01

Aspartic proteinase (EC 3.4.23) activity plays a pivotal role in the degradation of Theobroma cacao L. seed proteins during the fermentation step of cacao bean processing. Therefore, this enzyme is believed to be critical for the formation of the peptide and amino acid cocoa flavor precursors that occurs during fermentation. Using cDNA cloning and northern blot analysis, we show here that there are at least two distinct aspartic proteinase genes ( TcAP1 and TcAP2) expressed during cacao seed development. Both genes are expressed early during seed development and their mRNA levels decrease towards the end of seed maturation. TcAP2 is expressed at a much higher level than TcAP1, although the expression of TcAP1 increases slightly during germination. The proteins encoded by TcAP1 and TcAP2 are relatively different from each other (73% identity). This, and the fact that the two corresponding genes have different expression patterns, suggests that the TcAP1 and TcAP2 proteins may have different functions in the maturing seeds and during germination. Because the TcAP2 gene is expressed at a much higher level during seed development than TcAP1, it is likely that the TcAP2 protein is primarily responsible for the majority of the industrially important protein hydrolysis that occurs during cacao bean fermentation. Finally, TcAP2 has been functionally expressed in the yeast Yarrowia lipolytica. The secreted recombinant protein is able to hydrolyse bovine haemoglobin at acidic pH and is sensitive to pepstatin A, confirming that TcAP2 encodes an aspartic proteinase, and strongly suggests that this gene encodes the well-characterized aspartic proteinase of mature cacao seeds.

Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons of Aplysia

PubMed Central

Michael, Dan; Martin, Kelsey C.; Seger, Rony; Ning, Ming-Ming; Baston, Rene; Kandel, Eric R.

1998-01-01

Long-term facilitation of the connections between the sensory and motor neurons of the gill-withdrawal reflex in Aplysia requires five repeated pulses of serotonin (5-HT). The repeated pulses of 5-HT initiate a cascade of gene activation that leads ultimately to the growth of new synaptic connections. Several genes in this process have been identified, including the transcriptional regulators apCREB-1, apCREB-2, apC/EBP, and the cell adhesion molecule apCAM, which is thought to be involved in the formation of new synaptic connections. Here we report that the transcriptional regulators apCREB-2 and apC/EBP, as well as a peptide derived from the cytoplasmic domain of apCAM, are phosphorylated in vitro by Aplysia mitogen-activated protein kinase (apMAPK). We have cloned the cDNA encoding apMAPK and show that apMAPK activity is increased in sensory neurons treated with repeated pulses of 5-HT and by the cAMP pathway. These results suggest that apMAPK may participate with cAMP-dependent protein kinase during long-term facilitation in sensory cells by modifying some of the key elements involved in the consolidation of short- to long-lasting changes in synaptic strength. PMID:9465108

A peptide fragment of ependymin neurotrophic factor uses protein kinase C and the mitogen-activated protein kinase pathway to activate c-Jun N-terminal kinase and a functional AP-1 containing c-Jun and c-Fos proteins in mouse NB2a cells.

PubMed

Adams, David S; Hasson, Brendan; Boyer-Boiteau, Anne; El-Khishin, Adam; Shashoua, Victor E

2003-05-01

Ependymin (EPN) is a goldfish brain neurotrophic factor previously shown to function in a variety of cellular events related to long-term memory formation and neuronal regeneration. CMX-8933, an 8-amino-acid synthetic peptide fragment of EPN, was designed for aiding an investigation of the biological properties of this glycoprotein. We reported from previous studies that treatment of mouse neuroblastoma (NB2a) cultures with CMX-8933 promotes activation of transcription factor AP-1, a characteristic previously associated with the following full-length neurotrophic factors: nerve growth factor, neurotropin-3, and brain-derived neurotrophic factor. The CMX-8933-activated AP-1 specifically bound an AP-1 consensus probe and appeared to contain c-Jun and c-Fos protein components in antibody supershift experiments. Because AP-1 influences a variety of positive and negative cellular processes, determined in part by its exact protein composition and mechanism of activation, we extended these initial AP-1 observations in the current study to confirm the identity of the CMX-8933-activated c-Jun and c-Fos components. CMX-8933 increases the enzymatic activity of c-Jun N-terminal kinase (JNK), increases the phosphorylation of JNK and c-Jun proteins, and increases the cellular titers of c-Jun and c-Fos mRNAs. Furthermore, the AP-1 activated by CMX-8933 is functional, insofar as it transactivates both synthetic and natural AP-1-dependent reporter plasmids. Inhibition studies indicate that activation of the 8933-induced AP-1 occurs via the mitogen-activated protein kinase pathway. These data are in agreement with the recently proposed model for the conversion of short- to long-term synaptic plasticity and memory, in which a JNK-activated transcription factor AP-1, containing c-Jun and c-Fos components, functions at the top of a hierarchy of transcription factors known to regulate long-term neural plasticity. Copyright 2003 Wiley-Liss, Inc.

The effect of directional inertias added to pelvis and ankle on gait

PubMed Central

2013-01-01

Background Gait training robots should display a minimum added inertia in order to allow normal walking. The effect of inertias in specific directions is yet unknown. We set up two experiments to assess the effect of inertia in anteroposterior (AP) direction to the ankle and AP and mediolateral (ML) direction to the pelvis. Methods We developed an experimental setup to apply inertia in forward backward and or sideways directions. In two experiments nine healthy subjects walked on a treadmill at 1.5 km/h and 4.5 km/h with no load and with AP loads of 0.3, 1.55 and 3.5 kg to the left ankle in the first experiment and combinations of AP and ML loads on the pelvis (AP loads 0.7, 4.3 and 10.2 kg; ML loads 0.6, 2.3 and 5.3 kg). We recorded metabolic rate, EMG of major leg muscles, gait parameters and kinematics. Results & discussion Adding 1.55 kg or more inertia to the ankle in AP direction increases the pelvis acceleration and decreases the foot acceleration in AP direction both at speeds of 4.5 km/h. Adding 3.5 kg of inertia to the ankle also increases the swing time as well as AP motions of the pelvis and head-arms-trunk (HAT) segment. Muscle activity remains largely unchanged. Adding 10.2 kg of inertia to the pelvis in AP direction causes a significant decrease of the pelvis and HAT segment motions, particularly at high speeds. Also the sagittal back flexion increases. Lower values of AP inertia and ML inertias up to 5.3 kg had negligible effect. In general the found effects are larger at high speeds. Conclusions We found that inertia up to 2 kg at the ankle or 6 kg added to the pelvis induced significant changes, but since these changes were all within the normal inter subject variability we considered these changes as negligible for application as rehabilitation robotics and assistive devices. PMID:23597391

Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap4A Pathway in Immunologically Activated Mast Cells ▿

PubMed Central

Carmi-Levy, Irit; Motzik, Alex; Ofir-Birin, Yifat; Yagil, Zohar; Yang, Christopher Maolin; Kemeny, David Michael; Han, Jung Min; Kim, Sunghoon; Kay, Gillian; Nechushtan, Hovav; Suzuki, Ryo; Rivera, Juan; Razin, Ehud

2011-01-01

We recently reported that diadenosine tetraphosphate hydrolase (Ap4A hydrolase) plays a critical role in gene expression via regulation of intracellular Ap4A levels. This enzyme serves as a component of our newly described lysyl tRNA synthetase (LysRS)-Ap4A biochemical pathway that is triggered upon immunological challenge. Here we explored the mechanism of this enzyme's translocation into the nucleus and found its immunologically dependent association with importin beta. Silencing of importin beta prevented Ap4A hydrolase nuclear translocation and affected the local concentration of Ap4A, which led to an increase in microphthalmia transcription factor (MITF) transcriptional activity. Furthermore, immunological activation of mast cells resulted in dephosphorylation of Ap4A hydrolase, which changed the hydrolytic activity of the enzyme. PMID:21402779

I "hear" what you're "saying": Auditory perceptual simulation, reading speed, and reading comprehension.

PubMed

Zhou, Peiyun; Christianson, Kiel

2016-01-01

Auditory perceptual simulation (APS) during silent reading refers to situations in which the reader actively simulates the voice of a character or other person depicted in a text. In three eye-tracking experiments, APS effects were investigated as people read utterances attributed to a native English speaker, a non-native English speaker, or no speaker at all. APS effects were measured via online eye movements and offline comprehension probes. Results demonstrated that inducing APS during silent reading resulted in observable differences in reading speed when readers simulated the speech of faster compared to slower speakers and compared to silent reading without APS. Social attitude survey results indicated that readers' attitudes towards the native and non-native speech did not consistently influence APS-related effects. APS of both native speech and non-native speech increased reading speed, facilitated deeper, less good-enough sentence processing, and improved comprehension compared to normal silent reading.

A population-based study of severity in patients with acute on chronic pancreatitis.

PubMed

Akshintala, Venkata S; Hutfless, Susan M; Yadav, Dhiraj; Khashab, Mouen A; Lennon, Anne Marie; Makary, Martin A; Hirose, Kenzo; Andersen, Dana K; Kalloo, Anthony N; Singh, Vikesh K

2013-11-01

The objectives of this study were to evaluate the severity of patients with acute pancreatitis (AP) on chronic pancreatitis (CP) and compare this to patients with AP without CP. The Maryland Health Services database was queried for all adult inpatient discharges with a primary diagnosis of AP from 1994 to 2010. Acute pancreatitis on CP and AP without CP were defined by the presence of the associated diagnosis code for CP. Severity was defined as organ failure, intensive care unit stay, or mortality. Acute pancreatitis on CP accounted for 13.7% of all AP discharges (9747/70,944). The proportion of AP-on-CP discharges doubled during the study period (8.8% to 17.6%; P < 0.0001). When compared with patients with AP without CP, AP-on-CP patients were younger, were more likely to be male and black, had higher rates of alcohol and drug abuse, and had less severe disease with lower rates of mortality, organ failure, need for mechanical ventilation, and intensive care unit stay. Among AP-on-CP patients, significant predictors of severity included advanced age, weight loss, and 2 or more comorbidities. Patients with AP on CP have less severe disease than do those with AP without CP. Weight loss, advanced age, and comorbidity increase the risk of severity in patients with AP on CP.

The temperate Burkholderia phage AP3 of the Peduovirinae shows efficient antimicrobial activity against B. cenocepacia of the IIIA lineage.

PubMed

Roszniowski, Bartosz; Latka, Agnieszka; Maciejewska, Barbara; Vandenheuvel, Dieter; Olszak, Tomasz; Briers, Yves; Holt, Giles S; Valvano, Miguel A; Lavigne, Rob; Smith, Darren L; Drulis-Kawa, Zuzanna

2017-02-01

Burkholderia phage AP3 (vB_BceM_AP3) is a temperate virus of the Myoviridae and the Peduovirinae subfamily (P2likevirus genus). This phage specifically infects multidrug-resistant clinical Burkholderia cenocepacia lineage IIIA strains commonly isolated from cystic fibrosis patients. AP3 exhibits high pairwise nucleotide identity (61.7 %) to Burkholderia phage KS5, specific to the same B. cenocepacia host, and has 46.7-49.5 % identity to phages infecting other species of Burkholderia. The lysis cassette of these related phages has a similar organization (putative antiholin, putative holin, endolysin, and spanins) and shows 29-98 % homology between specific lysis genes, in contrast to Enterobacteria phage P2, the hallmark phage of this genus. The AP3 and KS5 lysis genes have conserved locations and high amino acid sequence similarity. The AP3 bacteriophage particles remain infective up to 5 h at pH 4-10 and are stable at 60 °C for 30 min, but are sensitive to chloroform, with no remaining infective particles after 24 h of treatment. AP3 lysogeny can occur by stable genomic integration and by pseudo-lysogeny. The lysogenic bacterial mutants did not exhibit any significant changes in virulence compared to wild-type host strain when tested in the Galleria mellonella moth wax model. Moreover, AP3 treatment of larvae infected with B. cenocepacia revealed a significant increase (P < 0.0001) in larvae survival in comparison to AP3-untreated infected larvae. AP3 showed robust lytic activity, as evidenced by its broad host range, the absence of increased virulence in lysogenic isolates, the lack of bacterial gene disruption conditioned by bacterial tRNA downstream integration site, and the absence of detected toxin sequences. These data suggest that the AP3 phage is a promising potent agent against bacteria belonging to the most common B. cenocepacia IIIA lineage strains.

The Micro-RNA172c-APETALA2-1 Node as a Key Regulator of the Common Bean-Rhizobium etli Nitrogen Fixation Symbiosis1[OPEN

PubMed Central

Nova-Franco, Bárbara; Íñiguez, Luis P.; Valdés-López, Oswaldo; Leija, Alfonso; Fuentes, Sara I.; Ramírez, Mario; Paul, Sujay

2015-01-01

Micro-RNAs are recognized as important posttranscriptional regulators in plants. The relevance of micro-RNAs as regulators of the legume-rhizobia nitrogen-fixing symbiosis is emerging. The objective of this work was to functionally characterize the role of micro-RNA172 (miR172) and its conserved target APETALA2 (AP2) transcription factor in the common bean (Phaseolus vulgaris)-Rhizobium etli symbiosis. Our expression analysis revealed that mature miR172c increased upon rhizobial infection and continued increasing during nodule development, reaching its maximum in mature nodules and decaying in senescent nodules. The expression of AP2-1 target showed a negative correlation with miR172c expression. A drastic decrease in miR172c and high AP2-1 mRNA levels were observed in ineffective nodules. Phenotypic analysis of composite bean plants with transgenic roots overexpressing miR172c or a mutated AP2-1 insensitive to miR172c cleavage demonstrated the pivotal regulatory role of the miR172 node in the common bean-rhizobia symbiosis. Increased miR172 resulted in improved root growth, increased rhizobial infection, increased expression of early nodulation and autoregulation of nodulation genes, and improved nodulation and nitrogen fixation. In addition, these plants showed decreased sensitivity to nitrate inhibition of nodulation. Through transcriptome analysis, we identified 114 common bean genes that coexpressed with AP2-1 and proposed these as being targets for transcriptional activation by AP2-1. Several of these genes are related to nodule senescence, and we propose that they have to be silenced, through miR172c-induced AP2-1 cleavage, in active mature nodules. Our work sets the basis for exploring the miR172-mediated improvement of symbiotic nitrogen fixation in common bean, the most important grain legume for human consumption. PMID:25739700

The micro-RNA72c-APETALA2-1 node as a key regulator of the common bean-Rhizobium etli nitrogen fixation symbiosis.

PubMed

Nova-Franco, Bárbara; Íñiguez, Luis P; Valdés-López, Oswaldo; Alvarado-Affantranger, Xochitl; Leija, Alfonso; Fuentes, Sara I; Ramírez, Mario; Paul, Sujay; Reyes, José L; Girard, Lourdes; Hernández, Georgina

2015-05-01

Micro-RNAs are recognized as important posttranscriptional regulators in plants. The relevance of micro-RNAs as regulators of the legume-rhizobia nitrogen-fixing symbiosis is emerging. The objective of this work was to functionally characterize the role of micro-RNA172 (miR172) and its conserved target APETALA2 (AP2) transcription factor in the common bean (Phaseolus vulgaris)-Rhizobium etli symbiosis. Our expression analysis revealed that mature miR172c increased upon rhizobial infection and continued increasing during nodule development, reaching its maximum in mature nodules and decaying in senescent nodules. The expression of AP2-1 target showed a negative correlation with miR172c expression. A drastic decrease in miR172c and high AP2-1 mRNA levels were observed in ineffective nodules. Phenotypic analysis of composite bean plants with transgenic roots overexpressing miR172c or a mutated AP2-1 insensitive to miR172c cleavage demonstrated the pivotal regulatory role of the miR172 node in the common bean-rhizobia symbiosis. Increased miR172 resulted in improved root growth, increased rhizobial infection, increased expression of early nodulation and autoregulation of nodulation genes, and improved nodulation and nitrogen fixation. In addition, these plants showed decreased sensitivity to nitrate inhibition of nodulation. Through transcriptome analysis, we identified 114 common bean genes that coexpressed with AP2-1 and proposed these as being targets for transcriptional activation by AP2-1. Several of these genes are related to nodule senescence, and we propose that they have to be silenced, through miR172c-induced AP2-1 cleavage, in active mature nodules. Our work sets the basis for exploring the miR172-mediated improvement of symbiotic nitrogen fixation in common bean, the most important grain legume for human consumption. © 2015 American Society of Plant Biologists. All Rights Reserved.

Action Potential Energy Efficiency Varies Among Neuron Types in Vertebrates and Invertebrates

PubMed Central

Sengupta, Biswa; Stemmler, Martin; Laughlin, Simon B.; Niven, Jeremy E.

2010-01-01

The initiation and propagation of action potentials (APs) places high demands on the energetic resources of neural tissue. Each AP forces ATP-driven ion pumps to work harder to restore the ionic concentration gradients, thus consuming more energy. Here, we ask whether the ionic currents underlying the AP can be predicted theoretically from the principle of minimum energy consumption. A long-held supposition that APs are energetically wasteful, based on theoretical analysis of the squid giant axon AP, has recently been overturned by studies that measured the currents contributing to the AP in several mammalian neurons. In the single compartment models studied here, AP energy consumption varies greatly among vertebrate and invertebrate neurons, with several mammalian neuron models using close to the capacitive minimum of energy needed. Strikingly, energy consumption can increase by more than ten-fold simply by changing the overlap of the Na+ and K+ currents during the AP without changing the APs shape. As a consequence, the height and width of the AP are poor predictors of energy consumption. In the Hodgkin–Huxley model of the squid axon, optimizing the kinetics or number of Na+ and K+ channels can whittle down the number of ATP molecules needed for each AP by a factor of four. In contrast to the squid AP, the temporal profile of the currents underlying APs of some mammalian neurons are nearly perfectly matched to the optimized properties of ionic conductances so as to minimize the ATP cost. PMID:20617202

Action potential energy efficiency varies among neuron types in vertebrates and invertebrates.

PubMed

Sengupta, Biswa; Stemmler, Martin; Laughlin, Simon B; Niven, Jeremy E

2010-07-01

The initiation and propagation of action potentials (APs) places high demands on the energetic resources of neural tissue. Each AP forces ATP-driven ion pumps to work harder to restore the ionic concentration gradients, thus consuming more energy. Here, we ask whether the ionic currents underlying the AP can be predicted theoretically from the principle of minimum energy consumption. A long-held supposition that APs are energetically wasteful, based on theoretical analysis of the squid giant axon AP, has recently been overturned by studies that measured the currents contributing to the AP in several mammalian neurons. In the single compartment models studied here, AP energy consumption varies greatly among vertebrate and invertebrate neurons, with several mammalian neuron models using close to the capacitive minimum of energy needed. Strikingly, energy consumption can increase by more than ten-fold simply by changing the overlap of the Na(+) and K(+) currents during the AP without changing the APs shape. As a consequence, the height and width of the AP are poor predictors of energy consumption. In the Hodgkin-Huxley model of the squid axon, optimizing the kinetics or number of Na(+) and K(+) channels can whittle down the number of ATP molecules needed for each AP by a factor of four. In contrast to the squid AP, the temporal profile of the currents underlying APs of some mammalian neurons are nearly perfectly matched to the optimized properties of ionic conductances so as to minimize the ATP cost.

Improvement of the Shock Absorption Ability of a Face Guard by Incorporating a Glass-Fiber-Reinforced Thermoplastic and Buffering Space

PubMed Central

Churei, Hiroshi; Takayanagi, Haruka; Iwasaki, Naohiko; Takahashi, Hidekazu; Uo, Motohiro

2018-01-01

This study aimed to evaluate the shock absorption ability of trial face guards (FGs) incorporating a glass-fiber-reinforced thermoplastic (GF) and buffering space. The mechanical properties of 3.2 mm and 1.6 mm thick commercial medical splint materials (Aquaplast, AP) and experimental GF prepared from 1.6 mm thick AP and fiberglass cloth were determined by a three-point bending test. Shock absorption tests were conducted on APs with two different thicknesses and two types of experimental materials, both with a bottom material of 1.6 mm thick AP and a buffering space of 30 mm in diameter (APS) and with either (i) 1.6 mm thick AP (AP-APS) or (ii)  1.6 mm thick GF (GF-APS) covering the APS. The GF exhibited significantly higher flexural strength (64.4 MPa) and flexural modulus (7.53 GPa) than the commercial specimens. The maximum load of GF-APS was 75% that of 3.2 mm AP, which is widely used clinically. The maximum stress of the GF-APS only could not be determined as its maximum stress is below the limits of the analysis materials used (<0.5 MPa). Incorporating a GF and buffering space would enhance the shock absorption ability; thus, the shock absorption ability increased while the total thickness and weight decreased. PMID:29854774

Improvement of the Shock Absorption Ability of a Face Guard by Incorporating a Glass-Fiber-Reinforced Thermoplastic and Buffering Space.

PubMed

Wada, Takahiro; Churei, Hiroshi; Takayanagi, Haruka; Iwasaki, Naohiko; Ueno, Toshiaki; Takahashi, Hidekazu; Uo, Motohiro

2018-01-01

This study aimed to evaluate the shock absorption ability of trial face guards (FGs) incorporating a glass-fiber-reinforced thermoplastic (GF) and buffering space. The mechanical properties of 3.2 mm and 1.6 mm thick commercial medical splint materials (Aquaplast, AP) and experimental GF prepared from 1.6 mm thick AP and fiberglass cloth were determined by a three-point bending test. Shock absorption tests were conducted on APs with two different thicknesses and two types of experimental materials, both with a bottom material of 1.6 mm thick AP and a buffering space of 30 mm in diameter (APS) and with either (i) 1.6 mm thick AP (AP-APS) or (ii)  1.6 mm thick GF (GF-APS) covering the APS. The GF exhibited significantly higher flexural strength (64.4 MPa) and flexural modulus (7.53 GPa) than the commercial specimens. The maximum load of GF-APS was 75% that of 3.2 mm AP, which is widely used clinically. The maximum stress of the GF-APS only could not be determined as its maximum stress is below the limits of the analysis materials used (<0.5 MPa). Incorporating a GF and buffering space would enhance the shock absorption ability; thus, the shock absorption ability increased while the total thickness and weight decreased.

Cdc2-like kinase 2 is a key regulator of the cell cycle via FOXO3a/p27 in glioblastoma.

PubMed

Park, Soon Young; Piao, Yuji; Thomas, Craig; Fuller, Gregory N; de Groot, John F

2016-05-03

Cdc2-like kinase 2 (CLK2) is known as a regulator of RNA splicing that ultimately controls multiple physiological processes. However, the function of CLK2 in glioblastoma progression has not been described. Reverse-phase protein array (RPPA) was performed to identify proteins differentially expressed in CLK2 knockdown cells compared to controls. The RPPA results indicated that CLK2 knockdown influenced the expression of survival-, proliferation-, and cell cycle-related proteins in GSCs. Thus, knockdown of CLK2 expression arrested the cell cycle at the G1 and S checkpoints in multiple GSC lines. Depletion of CLK2 regulated the dephosphorylation of AKT and decreased phosphorylation of Forkhead box O3a (FOXO3a), which not only translocated to the nucleus but also increased p27 expression. In two glioblastoma xenograft models, the survival duration of mice with CLK2-knockdown GSCs was significantly longer than mice with control tumors. Additionally, tumor volumes were significantly smaller in CLK2-knockdown mice than in controls. Knockdown of CLK2 expression reduced the phosphorylation of FOXO3a and decreased Ki-67 in vivo. Finally, high expression of CLK2 protien was significantly associated with worse patient survival. These findings suggest that CLK2 plays a critical role in controlling the cell cycle and survival of glioblastoma via FOXO3a/p27.

Cdc2-like kinase 2 is a key regulator of the cell cycle via FOXO3a/p27 in glioblastoma

PubMed Central

Thomas, Craig; Fuller, Gregory N.; de Groot, John F.

2016-01-01

Cdc2-like kinase 2 (CLK2) is known as a regulator of RNA splicing that ultimately controls multiple physiological processes. However, the function of CLK2 in glioblastoma progression has not been described. Reverse-phase protein array (RPPA) was performed to identify proteins differentially expressed in CLK2 knockdown cells compared to controls. The RPPA results indicated that CLK2 knockdown influenced the expression of survival-, proliferation-, and cell cycle-related proteins in GSCs. Thus, knockdown of CLK2 expression arrested the cell cycle at the G1 and S checkpoints in multiple GSC lines. Depletion of CLK2 regulated the dephosphorylation of AKT and decreased phosphorylation of Forkhead box O3a (FOXO3a), which not only translocated to the nucleus but also increased p27 expression. In two glioblastoma xenograft models, the survival duration of mice with CLK2-knockdown GSCs was significantly longer than mice with control tumors. Additionally, tumor volumes were significantly smaller in CLK2-knockdown mice than in controls. Knockdown of CLK2 expression reduced the phosphorylation of FOXO3a and decreased Ki-67 in vivo. Finally, high expression of CLK2 protien was significantly associated with worse patient survival. These findings suggest that CLK2 plays a critical role in controlling the cell cycle and survival of glioblastoma via FOXO3a/p27. PMID:27050366

Weight Gain and Its Correlates Among Forensic Inpatients

PubMed Central

Hilton, N Zoe; Ham, Elke; Lang, Carol; Harris, Grant T

2015-01-01

Objective: We investigated changes in weight, body mass index (BMI), and other indices of the metabolic syndrome in forensic inpatients. Weight gain associated with newer antipsychotics (APs) is well established in the general psychiatric population. Methods: We examined the medical records of 291 men admitted to a forensic hospital at admission and again at discharge or 365 days later if still in hospital. We also recorded diagnosis and smoker status on admission and quantified psychotropic treatment and adherence, physical activity, and daytime occupation during the hospitalization. Results: On admission, 33% were obese and 22% of the 106 patients for whom sufficient data were available met criteria for metabolic syndrome. Among patients staying at least 30 days, 60% were weighed again before discharge but repeated blood pressure and waist circumference measures were uncommon, even among those at greatest risk. The 122 forensic inpatients with sufficient information gained an average of 12% of their body weight and 40% increased by at least 1 BMI category, gaining an average of 3.67 kg per month. Weight gain was associated with duration of time and was not attributable to being underweight on admission, diagnosis of schizophrenia, atypical AP treatment, medication adherence, or having been a smoker. Conclusions: Patients gained weight during forensic hospitalization independent of medication use. We recommend further research using consistent measurement and wider sampling of both metabolic syndrome indicators and its individual and systemic causes in forensic populations. PMID:26174527

Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination

PubMed Central

Mortensen, Franziska; Schneider, Daniel; Barbic, Tanja; Sladewska-Marquardt, Anna; Kühnle, Simone; Marx, Andreas; Scheffner, Martin

2015-01-01

Deregulation of the ubiquitin ligase E6 associated protein (E6AP) encoded by the UBE3A gene has been associated with three different clinical pictures. Hijacking of E6AP by the E6 oncoprotein of distinct human papillomaviruses (HPV) contributes to the development of cervical cancer, whereas loss of E6AP expression or function is the cause of Angelman syndrome, a neurodevelopmental disorder, and increased expression of E6AP has been involved in autism spectrum disorders. Although these observations indicate that the activity of E6AP has to be tightly controlled, only little is known about how E6AP is regulated at the posttranslational level. Here, we provide evidence that the hydrophobic patch of ubiquitin comprising Leu-8 and Ile-44 is important for E6AP-mediated ubiquitination, whereas it does not affect the catalytic properties of the isolated catalytic HECT domain of E6AP. Furthermore, we show that the HPV E6 oncoprotein rescues the disability of full-length E6AP to use a respective hydrophobic patch mutant of ubiquitin for ubiquitination and that it stimulates E6AP-mediated ubiquitination of Ring1B, a known substrate of E6AP, in vitro and in cells. Based on these data, we propose that E6AP exists in at least two different states, an active and a less active or latent one, and that the activity of E6AP is controlled by noncovalent interactions with ubiquitin and allosteric activators such as the HPV E6 oncoprotein. PMID:26216987

Hydrocortisone at stress-associated concentrations helps maintain human heart rate variability during subsequent endotoxin challenge.

PubMed

Rassias, Athos J; Guyre, Paul M; Yeager, Mark P

2011-12-01

We evaluated the differential impact of stress-associated vs high pharmacologic concentrations of hydrocortisone pretreatment on heart rate variability (HRV) during a subsequent systemic inflammatory stimulus. Healthy volunteers were randomized to receive placebo (Control) and hydrocortisone at 1.5 μg/kg per minute (STRESS) or at 3.0 μg/kg per minute (PHARM) as a 6-hour infusion. The STRESS dose was chosen to replicate the condition of physiologic adrenal cortical output during acute systemic stress. The PHARM dose was chosen to induce a supraphysiologic concentration of cortisol. The next day, all subjects received 2 ng/kg Escherichia coli endotoxin (lipopolysaccharide). Heart rate variability was analyzed with the statistic approximate entropy (ApEn). A lower ApEn correlates with decreased HRV. At the 3-hour nadir, the decrease in ApEn in the STRESS group was significantly less compared to placebo (P < .03), whereas ApEn in the PHARM group was not statistically different. We also found that the maximal decrease in ApEn preceded maximal increase in heart rate in all groups. The decrease in R-R interval was maximal at 4 hours, whereas the ApEn nadir was 1 hour earlier at 3 hours. Pretreatment with a stress dose of hydrocortisone but not a higher pharmacologic dose maintained a significantly higher ApEn after endotoxin exposure when compared to a placebo. In addition, decreases in ApEn preceded increases in heart rate. Copyright © 2011 Elsevier Inc. All rights reserved.

National survey of fluid therapy in acute pancreatitis: current practice lacks a sound evidence base.

PubMed

Haydock, Matthew D; Mittal, Anubhav; van den Heever, Marc; Rossaak, Jeremy I; Connor, Saxon; Rodgers, Michael; Petrov, Maxim S; Windsor, John A

2013-10-01

Fluid therapy (FT) is a critical intervention in managing acute pancreatitis (AP). There is a paucity of evidence to guide FT and virtually no data on current prescribing practice. This survey aims to characterize current practice and opinion with regard to FT in AP throughout New Zealand. Information was collected on fluid selection, administration, and goal-directed FT. The survey was distributed online and in print to all doctors employed in General Surgery Departments in New Zealand on 1 May 2012. Monthly email reminders were sent for 6 months. The overall response rate was 47 % (n = 190/408). Crystalloids were the preferred initial fluid for all categories of severity; however, colloid use increased with severity (p < 0.001). Fluid volume also increased with severity (p = 0.001), with 74 % of respondents prescribing >4 L for AP with organ failure (OF). Clinicians treating 26-50 patients per year with AP were less likely to prescribe colloid for AP with OF (8 vs 43 %) (p = 0.001). Rate of fluid administration in AP with OF varied according to physicians' seniority (p = 0.004); consultants prescribed >4 L more than other groups (83 vs 68 %). Only 17 % of respondents reported the use of guidelines. This survey reveals significant variation in prescription of FT for AP, and aggressive FT is commonly prescribed for AP with OF. There is little adherence to published guidelines or best available evidence.

Regulation of CCN2/CTGF Expression in the Nucleus Pulposus of the Intervertebral Disc: Role of Smad and AP1 Signaling

PubMed Central

Tran, Cassie M.; Markova, Dessislava; Smith, Harvey E.; Susarla, Bala; Ponnappan, Ravi Kumar; Anderson, D Greg; Symes, Aviva; Shapiro, Irving M.; Risbud, Makarand V.

2011-01-01

Objective To investigate TGFβ regulation of CTGF expression in cells of the nucleus pulposus. Methods Real Time RT-PCR and Western blot analysis was used to measure CTGF expression in the nucleus pulposus. Transfections were used to measure the effect of Smad2/3/7 and AP1on TGFβ mediated CTGF promoter activity. Results CTGF expression was lower in the neonatal disc compared with the skeletally mature rat disc. An increase in CTGF expression and promoter activity was observed in nucleus pulposus cells after TGFβ treatment. Deletion analysis indicated that promoter constructs lacking smad and AP1 motifs were unresponsive to treatment. Analysis showed that full-length Smad3 and the Smad3-MH2 domain alone increased CTGF activity. Further evidence of Smad3 and AP1 involvement was seen when DN-Smad3, SiRNA-Smad3, smad7 and DN-AP1 suppressed TGFβ mediated activation of the CTGF promoter. When either Smad3 or AP1 sites were mutated, CTGF promoter induction by TGFβ was suppressed. We also observed a decrease in expression of CTGF in discs of Smad3 null mice compared to the wild type. Analysis of human nucleus pulposus indicated a trend of increasing CTGF and TGFβ expression in the degenerate state. Conclusion TGFβ, through Smad3 and AP1, serves as a positive regulator of CTGF expression in the nucleus pulposus. We propose that CTGF is a part of the limited reparative response of the degenerate disc. PMID:20222112

THE M-RNA, EXPRESSION OF SERCA2 AND NCX1 IN THE PROCESS OF PHARMACOLOGICAL CELL PROTECTION IN EXPERIMENTAL ACUTE PANCREATITIS INDUCED BY TAUROCHOLATE.

PubMed

Vasques, Enio Rodrigues; Cunha, José Eduardo Monteiro; Kubrusly, Marcia Saldanha; Coelho, Ana Maria; Sanpietri, Sandra N; Nader, Helena B; Tersariol, Ivarne L S; Lima, Marcelo A; Chaib, Eleazar; D'Albuquerque, Luiz Augusto Carneiro

2018-06-21

Intracellular calcium overload is known to be a precipitating factor of pancreatic cell injury in acute pancreatitis (AP). Intracellular calcium homeostasis depends of Plasmatic Membrane Calcium ATPase (PMCA), Sarcoplasmic Endothelial Reticulum Calcium ATPase 2 (SERCA 2) and the Sodium Calcium Exchanger (NCX1). The antioxidant melatonin (Mel) and Trisulfate Disaccharide (TD) that accelerates NCX1 action could reduce the cell damage determined by the AP. To evaluate m-RNA expressions of SERCA2 and NCX1 in acute pancreatitis induced by sodium taurocholate in Wistar rats pre-treated with melatonin and/or TD. Wistar rats were divided in groups: 1) without AP; 2) AP without pre-treatment; 3) AP and Melatonin; 4) AP and TD; 5) AP and Melatonin associated to TD. Pancreatic tissue samples were collected for detection of SERCA2 and NCX1 m-R NA levels by polymerase chain reaction (PCR). Increased m-RNA expression of SERCA2 in the melatonin treated group, without increase of m-RNA expression of the NCX1. The TD did not affect levels of SERCA2 and NCX1 m-RNA expressions. The combined melatonin and TD treatment reduced the m-RNA expression of SERCA2. The effect of melatonin is restricted to increased m-RNA expression of SERCA2. Although TD does not affect gene expression, its action in accelerating calcium exchanger function can explain the slightest expression of SERCA2 m-RNA when associated with Melatonin, perhaps by a joint action of drugs with different and but possibly complementary mechanisms.

An Approach Toward Synthesis of Bridgmanite in Dynamic Compression Experiments

NASA Astrophysics Data System (ADS)

Reppart, J. J.

2015-12-01

Bridgmanite occurs in heavily shocked meteorites and provides a useful constraint on pressure-temperature conditions during shock-metamorphism. Its occurrence also provides constraints on the shock release path. Shock-release and shock duration are important parameters in estimating the size of impactors that generate the observed shock metamorphic record. Thus, it is timely to examine if bridgmanite can be synthesized in dynamic compression experiments with the goal of establishing a correlation between shock duration and grainsize. Up to now only one high pressure polymorph of an Mg-silicate has been synthesized AND recovered in a shock experiment (wadsleyite). Therefore, it is not given that shock synthesis of bridgmanite is possible. This project started recently, so we present an outline of shock experiment designs and potentially results from the first experiments. FUNDING ACKNOWLEDGMENT UNLV HiPSEC: This research was sponsored (or sponsored in part) by the National Nuclear Security Administration under the Stewardship Science Academic Alliances program through DOE Cooperative Agreement #DE-NA0001982. HPCAT: "[Portions of this work were]/[This work was] performed at HPCAT (Sector 16), Advanced Photon Source (APS), Argonne National Laboratory. HPCAT operations are supported by DOE-NNSA under Award No. DE-NA0001974 and DOE-BES under Award No. DE-FG02-99ER45775, with partial instrumentation funding by NSF. APS is supported by DOE-BES, under Contract No. DE-AC02-06CH11357."

Developments in Assisting Countries in Implementing the IAEA Additional Protocol

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

Killinger, Mark H.; Hansen, Linda H.; Cain, Ronald A.

In 2008, the U.S. Department of Energy (DOE) began assisting selected non-nuclear weapon states in planning and preparing for implementation of the International Atomic Energy Agency’s Additional Protocol (AP). Since then, the AP international implementation program has contributed to the substantial progress made by Vietnam, Thailand, Iraq, and Malaysia in preparing for entry-into-force of the AP. An overall engagement plan has been developed with components designed to train government AP implementing agencies, inform policy makers, conduct outreach to industry and universities, make AP reporting software available and useful, and plan a detailed approach for implementing the declaration and complementary accessmore » provisions of the AP. DOE recently began collaborating with Indonesia, which has already entered the AP into force, requiring a second method of engagement somewhat different from that taken with countries that have not entered the AP into force. The AP international implementation program, administered by the International Nuclear Safeguards and Engagement Program, is working more closely with DOE’s International Nonproliferation Export Control Program to ensure countries are aware of and prepared to implement the export/import provisions of the AP. As the AP implementation program matures and helps move countries closer to entry-into-force or improved AP implementation, it is identifying characteristics of a country’s “end-state” that indicate that DOE assistance is no longer required. The U.S. AP Implementation Act and Senate Resolution of Ratification require the Administration to report annually to Congress on measures taken to achieve the adoption of the AP in non-nuclear weapon states. DOE’s AP international implementation program is a significant part of these measures. This paper describes recent developments to increase the scope and effectiveness of the program.« less

The effect of signal acquisition and processing choices on ApEn values: towards a "gold standard" for distinguishing effort levels from isometric force records.

PubMed

Forrest, Sarah M; Challis, John H; Winter, Samantha L

2014-06-01

Approximate entropy (ApEn) is frequently used to identify changes in the complexity of isometric force records with ageing and disease. Different signal acquisition and processing parameters have been used, making comparison or confirmation of results difficult. This study determined the effect of sampling and parameter choices by examining changes in ApEn values across a range of submaximal isometric contractions of the first dorsal interosseus. Reducing the sample rate by decimation changed both the value and pattern of ApEn values dramatically. The pattern of ApEn values across the range of effort levels was not sensitive to the filter cut-off frequency, or the criterion used to extract the section of data for analysis. The complexity increased with increasing effort levels using a fixed 'r' value (which accounts for measurement noise) but decreased with increasing effort level when 'r' was set to 0.1 of the standard deviation of force. It is recommended isometric force records are sampled at frequencies >200Hz, template length ('m') is set to 2, and 'r' set to measurement system noise or 0.1SD depending on physiological process to be distinguished. It is demonstrated that changes in ApEn across effort levels are related to changes in force gradation strategy. Copyright © 2014 IPEM. Published by Elsevier Ltd. All rights reserved.

Apical Periodontitis and Endodontic Treatment in Patients with Type II Diabetes Mellitus: Comparative Cross-sectional Survey.

PubMed

Smadi, Leena

2017-05-01

The aims of this study were to investigate the prevalence of apical periodontitis (AP) in diabetes mellitus (DM) patients compared with nondiabetic patients and to examine the effect of glycemic control on the prevalence of AP. Radiographs of a group of DM patients were compared with those of a matched nondiabetic group to identify AP. The diabetic group was subdivided according to the level of glycemic control into two subgroups: A well-controlled DM and a poorly controlled DM. The periapical index score was used to assess the periapical status. All groups were compared in regard to the presence of AP lesions, the number of end-odontically treated teeth (ET), and the percentage of failure of endodontically treated teeth (AP/ET ratio). Statistical Package for the Social Sciences (SPSS version 20.0, Chicago, Illinois, USA) was used for all the analyses; p ≤ 0.05 was considered as statistically significant. The prevalence of AP was higher in diabetic group than in the nondiabetic group (13.5 vs 11.9% respectively). Diabetic group had more teeth with endodontic treatment ET compared with nondiabetic group (4.18 vs 1.82% respectively); this difference was statistically significant (p = 0.001) along with higher AP/ET ratio (27.7 vs 19.3 respectively). The poorly controlled DM group had a higher prevalence of AP lesions compared with the well-controlled DM group (18.29 vs 9.21 respectively). This difference was statistically significant (p = 0.001); they also had a higher percentage of ET (5.55 vs 3.13% respectively) and AP/ ET ratio (32.0 vs 21.8% respectively). This survey demonstrates a higher prevalence of AP in DM patients compared with nondiabetic group, with an increased prevalence of persistent chronic AP. Compared with a well-controlled diabetic group, a poor glycemic control may be associated with a higher prevalence of AP and increased rate of endodontic failures. Counseling diabetic patients, particularly those with poor glycemic control, about the risk of failure of endodontic treatment can be part of planning management, which could include refereeing diabetic patients who need endodontic treatment for consultant care.

NOS1AP is associated with increased severity of PTSD and depression in untreated combat veterans.

PubMed

Lawford, Bruce R; Morris, Charles P; Swagell, Christopher D; Hughes, Ian P; Young, Ross McD; Voisey, Joanne

2013-05-01

Posttraumatic stress disorder (PTSD) and depressive disorder are over represented in combat veterans. Veterans with both disorders have an increased risk of suicide. The nitric oxide synthase 1 adaptor protein (NOS1AP) gene, which modulates stress-evoked N-methyl-d-aspartate (NMDA) activity, was investigated in combat veterans. A comprehensive genetic analysis of NOS1AP and its association with PTSD was investigated in Vietnam combat veterans with PTSD (n=121) and a group of healthy control individuals (n=237). PTSD patients were assessed for symptom severity and level of depression using the Mississippi Scale for Combat-Related PTSD and the Beck Depression Inventory-II (BDI). The G allele of NOS1AP SNP rs386231 was significantly associated with PTSD (p=0.002). Analysis of variance revealed significant differences in BDI-II and Mississippi scores between genotypes for rs386231 with the GG genotype associated with increased severity of depression (p=0.002 F=6.839) and higher Mississippi Scale for Combat-Related PTSD scores (p=0.033). Haplotype analysis revealed that the C/G haplotype (rs451275/rs386231) was significantly associated with PTSD (p=0.001). The sample sizes in our study were not sufficient to detect SNP associations with very small effects. In addition the study was limited by its cross sectional design. This is the first study reporting that a variant of the NOS1AP gene is associated with PTSD. Our data also suggest that a genetic variant in NOS1AP may increase the susceptibility to severe depression in patients with PTSD and increased risk for suicide. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

The role of early life growth development, the FTO gene and exclusive breastfeeding on child BMI trajectories.

PubMed

Wu, Yan Yan; Lye, Stephen; Briollais, Laurent

2017-10-01

Recent studies have implicated the FTO gene in child and adult obesity. A longer duration of exclusive breastfeeding (EXBF) has been shown to reduce body mass index (BMI) and the risk of being overweight in the general population and among FTO gene carriers. However, it remains unclear whether the preventive effect of EXBF could be explained by its impact on early life growth development, e.g. ages at adiposity peak (AP) and adiposity rebound (AR) and BMI velocities in the first years of life, which are major determinants of overweight and obesity later in life. We studied 5590 children from the British Avon Longitudinal Study of Parents and Children (ALSPAC) cohort and modelled their longitudinal BMI profiles with mixed effects models from birth to 16 years of age, as well as their ages at AP, AR and BMI velocities in relation to the FTO gene variant and EXBF. A longer duration of EXBF (i.e. at least 5 months) has substantial impact on BMI growth trajectories among children carrying the FTO adverse variant by modulating the age at AP, age at AR and BMI velocities. EXBF acts antagonistically to the FTO rs9939609 risk allele and by the age of 15, the predicted reduction in BMI after 5 months of EXBF is 0.56 kg/m2 [95% confidence interval (CI) 0.11-1.01; P = 0.003] and 1.14 kg/m2 (95% CI 0.67-1.62; P < 0.0001) in boys and girls, respectively. EXBF influences early life growth development and thus plays a critical role in preventing the risks of overweight and obesity even when those are exacerbated by genetic factors. © The Author 2017; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation.

PubMed

Karimpour, Shervin; Lou, Junyang; Lin, Lilie L; Rene, Luis M; Lagunas, Lucio; Ma, Xinrong; Karra, Sreenivasu; Bradbury, C Matthew; Markovina, Stephanie; Goswami, Prabhat C; Spitz, Douglas R; Hirota, Kiichi; Kalvakolanu, Dhananjaya V; Yodoi, Junji; Gius, David

2002-09-12

A recently identified class of signaling factors uses critical cysteine motif(s) that act as redox-sensitive 'sulfhydryl switches' to reversibly modulate specific signal transduction cascades regulating downstream proteins with similar redox-sensitive sites. For example, signaling factors such as redox factor-1 (Ref-1) and transcription factors such as the AP-1 complex both contain redox-sensitive cysteine motifs that regulate activity in response to oxidative stress. The mammalian thioredoxin reductase-1 (TR) is an oxidoreductase selenocysteine-containing flavoprotein that also appears to regulate multiple downstream intracellular redox-sensitive proteins. Since ionizing radiation (IR) induces oxidative stress as well as increases AP-1 DNA-binding activity via the activation of Ref-1, the potential roles of TR and thioredoxin (TRX) in the regulation of AP-1 activity in response to IR were investigated. Permanently transfected cell lines that overexpress wild type TR demonstrated constitutive increases in AP-1 DNA-binding activity as well as AP-1-dependent reporter gene expression, relative to vector control cells. In contrast, permanently transfected cell lines expressing a TR gene with the active site cysteine motif deleted were unable to induce AP-1 activity or reporter gene expression in response to IR. Transient genetic overexpression of either the TR wild type or dominant-negative genes demonstrated similar results using a transient assay system. One mechanism through which TR regulates AP-1 activity appears to involve TRX sub-cellular localization, with no change in the total TRX content of the cell. These results identify a novel function of the TR enzyme as a signaling factor in the regulation of AP-1 activity via a cysteine motif located in the protein.

Cannabis-Induced Acute Pancreatitis: A Systematic Review.

PubMed

Barkin, Jodie A; Nemeth, Zsuzsanna; Saluja, Ashok K; Barkin, Jamie S

2017-09-01

Cannabis is the most frequently consumed illicit drug in the world, with higher prevalence under the age of 35 years. Cannabis was first reported as a possible cause of acute pancreatitis (AP) in 2004. The aim of this systematic review is to examine cannabis use as an etiology of AP. A search using PubMed/Medline, Embase, Scopus, and Cochrane was performed without language or year limitations to May 1, 2016. Search terms were "Cannabis" and "Acute Pancreatitis" with all permutations. The search yielded 239 results. Acute pancreatitis was defined by meeting 2 of 3 Revised Atlanta Classification criteria. Cannabis-induced AP was defined by preceding use of cannabis and exclusion of common causes of AP when reported. Sixteen papers met inclusion criteria dating from 2004 to 2016. There were 26 cases of cannabis-induced AP (23/26 men; 24/26 under the age of 35 y). Acute pancreatitis correlated with increased cannabis use in 18 patients. Recurrent AP related temporally to cannabis use was reported in 15 of 26. There are 13 reports of no further AP episodes after cannabis cessation. Cannabis is a possible risk factor for AP and recurrent AP, occurring primarily in young patients under the age of 35 years. Toxicology screens should be considered in all patients with idiopathic AP.

Alkaline Phosphatase-Positive Immortal Mouse Embryo Fibroblasts Are Cells in a Transitional Reprogramming State Induced to Face Environmental Stresses.

PubMed

Evangelista, Monica; Baroudi, Mariama El; Rizzo, Milena; Tuccoli, Andrea; Poliseno, Laura; Pellegrini, Marco; Rainaldi, Giuseppe

2015-01-01

In this study, we report that immortal mouse embryonic fibroblasts (I-MEFs) have a baseline level of cells positive for alkaline phosphatase (AP(+)) staining. Environmental stresses, including long-lasting growth in the absence of expansion and treatment with drugs, enhance the frequency of AP(+) I-MEFs. By adapting fast red AP staining to the sorting procedure, we separated AP(+) and AP(-) I-MEFs and demonstrated that the differentially expressed genes are consistent with a reprogrammed phenotype. In particular, we found that sestrin 1 is upregulated in AP(+) I-MEFs. We focused on this gene and demonstrated that increased sestrin 1 expression is accompanied by the growth of I-MEFs in the absence of expansion and occurs before the formation of AP(+) I-MEFs. Together with sestrin 1 upregulation, we found that AP(+) I-MEFs accumulated in the G1 phase of the cell cycle, suggesting that the two events are causally related. Accordingly, we found that silencing sestrin 1 expression reduced the frequency and G1 accumulation of AP(+) I-MEFs. Taken together, our data suggested that I-MEFs stressed by environmental changes acquire the AP(+) phenotype and achieve a quiescent state characterized by a new transcriptional network.

HS-SPME-GC-MS/MS Method for the Rapid and Sensitive Quantitation of 2-Acetyl-1-pyrroline in Single Rice Kernels.

PubMed

Hopfer, Helene; Jodari, Farman; Negre-Zakharov, Florence; Wylie, Phillip L; Ebeler, Susan E

2016-05-25

Demand for aromatic rice varieties (e.g., Basmati) is increasing in the US. Aromatic varieties typically have elevated levels of the aroma compound 2-acetyl-1-pyrroline (2AP). Due to its very low aroma threshold, analysis of 2AP provides a useful screening tool for rice breeders. Methods for 2AP analysis in rice should quantitate 2AP at or below sensory threshold level, avoid artifactual 2AP generation, and be able to analyze single rice kernels in cases where only small sample quantities are available (e.g., breeding trials). We combined headspace solid phase microextraction with gas chromatography tandem mass spectrometry (HS-SPME-GC-MS/MS) for analysis of 2AP, using an extraction temperature of 40 °C and a stable isotopologue as internal standard. 2AP calibrations were linear between the concentrations of 53 and 5380 pg/g, with detection limits below the sensory threshold of 2AP. Forty-eight aromatic and nonaromatic, milled rice samples from three harvest years were screened with the method for their 2AP content, and overall reproducibility, observed for all samples, ranged from 5% for experimental aromatic lines to 33% for nonaromatic lines.

Experience-dependent increase in spine calcium evoked by backpropagating action potentials in layer 2/3 pyramidal neurons in rat somatosensory cortex.

PubMed

Krieger, Patrik

2009-11-01

In spines on basal dendrites of layer 2/3 pyramidal neurons in somatosensory barrel cortex, calcium transients evoked by back-propagating action potentials (bAPs) were investigated (i) along the length of the basal dendrite, (ii) with postnatal development and (iii) with sensory deprivation during postnatal development. Layer 2/3 pyramidal neurons were investigated at three different ages. At all ages [postnatal day (P)8, P14, P21] the bAP-evoked calcium transient amplitude increased with distance from the soma with a peak at around 50 microm, followed by a gradual decline in amplitude. The effect of sensory deprivation on the bAP-evoked calcium was investigated using two different protocols. When all whiskers on one side of the rat snout were trimmed daily from P8 to P20-24 there was no difference in the bAP-evoked calcium transient between cells in the contralateral hemisphere, lacking sensory input from the whisker, and cells in the ipsilateral barrel cortex, with intact whisker activation. When, however, only the D-row whiskers on one side were trimmed the distribution of bAP-evoked calcium transients in spines was shifted towards larger amplitudes in cells located in the deprived D-column. In conclusion, (i) the bAP-evoked calcium transient gradient along the dendrite length is established at P8, (ii) the calcium transient increases in amplitude with age and (iii) this increase is enhanced in layer 2/3 pyramidal neurons located in a sensory-deprived barrel column that is bordered by non-deprived barrel columns.

Atypical Femoral Shaft Fractures in Female Bisphosphonate Users Were Associated with an Increased Anterolateral Femoral Bow and a Thicker Lateral Cortex: A Case-Control Study.

PubMed

Jang, Seung Pil; Yeo, Ingwon; So, Sang-Yeon; Kim, Keunbyuel; Moon, Young-Wan; Park, Youn-Soo; Lim, Seung-Jae

2017-01-01

The purpose of our study was to investigate the radiographic characteristics of atypical femoral shaft fractures (AFSFs) in females with a particular focus on femoral bow and cortical thickness. We performed a fracture location-, age-, gender-, and ethnicity-matched case-control study. Forty-two AFSFs in 29 patients and 22 typical osteoporotic femoral shaft fractures in 22 patients were enrolled in AFSF group and control group, respectively. With comparing demographics between two groups, radiographically measured femoral bow and cortical thicknesses of AFSF group were compared with control group. All AFSF patients were females with a mean age of 74.4 years (range, 58-85 years). All had a history of bisphosphonate (BP) use with a mean duration of 7.3 years (range 1-17 years). Femoral bow of AFSF group was significantly higher than control group on both anteroposterior (AP) and lateral radiographs after age correction. Mean femoral bow on an AP radiograph was 12.39° ± 5.38° in AFSF group and 3.97 ± 3.62° in control group ( P < 0.0001). Mean femoral bow on the lateral radiograph was 15.71° ± 5.62° in AFSF group and 10.72° ± 4.61° in control group (after age correction P = 0.003). And cortical thicknesses of AFSF group demonstrated marked disparity between tensile and compressive side of bowed femurs in this study. An adjusted lateral cortical thickness was 10.5 ± 1.4 mm in AFSF group and 8.1 ± 1.3 mm in control group (after age correction P < 0.0001) while medial cortical thickness of AFSF group was not statistically different from control group. Correlation analysis showed that the lateral femoral bow on the AP radiograph was solely related to lateral CTI ( R = 0.378, P = 0.002). AFSFs in female BP users were associated with an increased anterolateral femoral bow and a thicker lateral cortex of femurs.

Triggered intracellular calcium waves in dog and human left atrial myocytes from normal and failing hearts.

PubMed

Aistrup, Gary L; Arora, Rishi; Grubb, Søren; Yoo, Shin; Toren, Benjamin; Kumar, Manvinder; Kunamalla, Aaron; Marszalec, William; Motiwala, Tej; Tai, Shannon; Yamakawa, Sean; Yerrabolu, Satya; Alvarado, Francisco J; Valdivia, Hector H; Cordeiro, Jonathan M; Shiferaw, Yohannes; Wasserstrom, John Andrew

2017-11-01

Abnormal intracellular Ca2+ cycling contributes to triggered activity and arrhythmias in the heart. We investigated the properties and underlying mechanisms for systolic triggered Ca2+ waves in left atria from normal and failing dog hearts. Intracellular Ca2+ cycling was studied using confocal microscopy during rapid pacing of atrial myocytes (36 °C) isolated from normal and failing canine hearts (ventricular tachypacing model). In normal atrial myocytes (NAMs), Ca2+ waves developed during rapid pacing at rates ≥ 3.3 Hz and immediately disappeared upon cessation of pacing despite high sarcoplasmic reticulum (SR) load. In heart failure atrial myocytes (HFAMs), triggered Ca2+ waves (TCWs) developed at a higher incidence at slower rates. Because of their timing, TCW development relies upon action potential (AP)-evoked Ca2+ entry. The distribution of Ca2+ wave latencies indicated two populations of waves, with early events representing TCWs and late events representing conventional spontaneous Ca2+ waves. Latency analysis also demonstrated that TCWs arise after junctional Ca2+ release has occurred and spread to non-junctional (cell core) SR. TCWs also occurred in intact dog atrium and in myocytes from humans and pigs. β-adrenergic stimulation increased Ca2+ release and abolished TCWs in NAMs but was ineffective in HFAMs making this a potentially effective adaptive mechanism in normals but potentially arrhythmogenic in HF. Block of Ca-calmodulin kinase II also abolished TCWs, suggesting a role in TCW formation. Pharmacological manoeuvres that increased Ca2+ release suppressed TCWs as did interventions that decreased Ca2+ release but these also severely reduced excitation-contraction coupling. TCWs develop during the atrial AP and thus could affect AP duration, producing repolarization gradients and creating a substrate for reentry, particularly in HF where they develop at slower rates and a higher incidence. TCWs may represent a mechanism for the initiation of atrial fibrillation particularly in HF. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

Transient voltage-dependent potassium currents are reduced in NTS neurons isolated from renal wrap hypertensive rats.

PubMed

Belugin, Sergei; Mifflin, Steve

2005-12-01

Whole cell patch-clamp measurements were made in neurons enzymatically dispersed from the nucleus of the solitary tract (NTS) to determine if alterations occur in voltage-dependent potassium channels from rats made hypertensive (HT) by unilateral nephrectomy/renal wrap for 4 wk. Some rats had the fluorescent tracer DiA applied to the aortic nerve before the experiment to identify NTS neurons receiving monosynaptic baroreceptor afferent inputs. Mean arterial pressure (MAP) was greater in 4-wk HT (165 +/- 5 mmHg, n = 26, P < 0.001) rats compared with normotensive (NT) rats (109 +/- 3 mmHg measured in 10 of 69 rats). Transient outward currents (TOCs) were observed in 67-82% of NTS neurons from NT and HT rats. At activation voltages from -10 to +10 mV, TOCs were significantly less in HT neurons compared with those observed in NT neurons (P < 0.001). There were no differences in the voltage-dependent activation kinetics, the voltage dependence of steady-state inactivation, and the rise and decay time constants of the TOCs comparing neurons isolated from NT and HT rats. The 4-aminopyridine-sensitive component of the TOC was significantly less in neurons from HT compared with NT rats (P < 0.001), whereas steady-state outward currents, whether or not sensitive to 4-aminopyridine or tetraethylammonium, were not different. Delayed excitation, studied under current clamp, was observed in 60-80% of NTS neurons from NT and HT rats and was not different comparing neurons from NT and HT rats. However, examination of the subset of NTS neurons exhibiting somatic DiA fluorescence revealed that DiA-labeled neurons from HT rats had a significantly shorter duration delayed excitation (n = 8 cells, P = 0.022) than DiA-labeled neurons from NT rats (n = 7 cells). Neurons with delayed excitation from HT rats had a significantly broader first action potential (AP) and a slower maximal downstroke velocity of repolarization compared with NT neurons with delayed excitation (P = 0.016 and P = 0.014, respectively). The number of APs in the first 200 ms of a sustained depolarization was greater in HT than NT neurons (P = 0.012). These results suggest that HT of 4-wk duration reduces TOCs in NTS neurons, and this contributes to reduced delayed excitation and increased AP responses to depolarizing inputs. Such changes could alter baroreflex function in hypertension.

Diadenosine tetraphosphate stimulates atrial ANP release via A(1) receptor: involvement of K(ATP) channel and PKC.

PubMed

Yuan, Kuichang; Cao, Chunhua; Bai, Guang Yi; Kim, Sung Zoo; Kim, Suhn Hee

2007-07-01

Diadenosine polyphosphates (APnAs) are endogenous compounds and exert diverse cardiovascular functions. However, the effects of APnAs on atrial ANP release and contractility have not been studied. In this study, the effects of diadenosine tetraphosphate (AP4A) on atrial ANP release and contractility, and their mechanisms were studied using isolated perfused rat atria. Treatment of atria with AP4A resulted in decreases in atrial contractility and extracellular fluid (ECF) translocation whereas ANP secretion and cAMP levels in perfusate were increased in a dose-dependent manner. These effects of AP4A were attenuated by A(1) receptor antagonist but not by A(2A) or A(3) receptor antagonist. Other purinoceptor antagonists also did not show any effects on AP4A-induced ANF release and contractility. The increment of ANP release and negative inotropy induced by AP4A was similar to those induced by AP3A, AP5A, and AP6A. Protein kinase A inhibitors accentuated AP4A-induced ANP secretion. In contrast, an inhibitor of phospholipase C, protein kinase C or sarcolemma K(ATP) channel completely blocked AP4A-induced ANP secretion. However, an inhibitor of adenylyl cyclase or mitochondria K(ATP) channel had no significant modification of AP4A effects. These results suggest that AP4A regulates atrial inotropy and ANP release mainly through A(1) receptor signaling involving phospholipase C-protein kinase C and sarcolemmal K(ATP) channel and that protein kinase A negatively modulates the effects of AP4A.

Antiseizure Effects of Ketogenic Diet on Seizures Induced with Pentylenetetrazole, 4-Aminopyridine and Strychnine in Wistar Rats.

PubMed

Sanya, E O; Soladoye, A O; Desalu, O O; Kolo, P M; Olatunji, L A; Olarinoye, J K

2017-03-06

The ketogenic diet (KD) is a cheap and effective alternative therapy for most epilepsy. There are paucity of experimental data in Nigeria on the usefulness of KD in epilepsy models. This is likely to be responsible for the poor clinical acceptability of the diet in the country. This study therefore aimed at providing experimental data on usefulness of KD on seizure models.  The study used 64 Wistar rats that were divided into two dietary groups [normal diet (ND) and ketogenic diet (KD)]. Animal in each group were fed for 35days. Medium chain triglyceride ketogenic diet (MCT-KD) was used and it consisted of 15% carbohydrate in normal rat chow long with 5ml sunflower oil (25% (v/w). The normal diet was the usual rat chow. Seizures were induced with one of Pentelyntetrazole (PTZ), 4-Aminopyridine (AP) and Strychnine (STR). Fasting glucose, ketosis level and serum chemistry were determined and seizure parameters recorded. Serum ketosis was significantly higher in MCT-KD-fed rats (12.7 ±2.6) than ND-fed (5.17±0.86) rats. Fasting blood glucose was higher in ND-fed rats (5.3±0.9mMol/l) than in MCT-KD fed rats (5.1±0.5mMol/l) with p=0.9. Seizure latency was significantly prolonged in ND-fed compared with MCT-KD fed rats after PTZ-induced seizures (61±9sec vs 570±34sec) and AP-induced seizures (49±11sec vs 483±41sec). The difference after Str-induced seizure (51±7 vs 62±8 sec) was not significan. The differences in seizure duration between ND-fed and MCT-KD fed rats with PTZ (4296±77sec vs 366±46sec) and with AP (5238±102sec vs 480±67sec) were significant (p<0.05), but not with STR (3841±94sec vs 3510±89sec) respectively. The mean serum Na+ was significantly higher in MCT-KD fed (141.7±2.1mMol/l) than ND-fed rats (137±2.3mMol/l). There was no significant difference in mean values of other serum electrolytes between the MCT-KD fed and ND-fed animals. MCT-KD caused increase resistance to PTZ-and AP-induced seizures, but has no effect on STR-induced seizures. This antiseizure property is probably mediated through GABAergic receptors (PTZ effect) and blockade of membrane bound KATP channels (AP effect) with some enhancement by serum ketosis.

Alkaline Phosphatase, an Unconventional Immune Protein.

PubMed

Rader, Bethany A

2017-01-01

Recent years have seen an increase in the number of studies focusing on alkaline phosphatases (APs), revealing an expanding complexity of function of these enzymes. Of the four human AP (hAP) proteins, most is known about tissue non-specific AP (TNAP) and intestinal AP (IAP). This review highlights current understanding of TNAP and IAP in relation to human health and disease. TNAP plays a role in multiple processes, including bone mineralization, vitamin B6 metabolism, and neurogenesis, is the genetic cause of hypophosphatasia, influences inflammation through regulation of purinergic signaling, and has been implicated in Alzheimer's disease. IAP regulates fatty acid absorption and has been implicated in the regulation of diet-induced obesity and metabolic syndrome. IAP and TNAP can dephosphorylate bacterial-derived lipopolysaccharide, and IAP has been identified as a potential regulator of the composition of the intestinal microbiome, an evolutionarily conserved function. Endogenous and recombinant bovine APs and recombinant hAPs are currently being explored for their potential as pharmacological agents to treat AP-associated diseases and mitigate multiple sources of inflammation. Continued research on these versatile proteins will undoubtedly provide insight into human pathophysiology, biochemistry, and the human holobiont.

An Autologous Protein Solution prepared from the blood of osteoarthritic patients contains an enhanced profile of anti-inflammatory cytokines and anabolic growth factors

PubMed Central

O'Shaughnessey, Krista; Matuska, Andrea; Hoeppner, Jacy; Farr, Jack; Klaassen, Mark; Kaeding, Christopher; Lattermann, Christian; King, William; Woodell-May, Jennifer

2014-01-01

The objective of this clinical study was to test if blood from osteoarthritis (OA) patients (n = 105) could be processed by a device system to form an autologous protein solution (APS) with preferentially increased concentrations of anti-inflammatory cytokines compared to inflammatory cytokines. To address this objective, APS was prepared from patients exhibiting radiographic evidence of knee OA. Patient metrics were collected including: demographic information, medical history, medication records, and Knee Injury and Osteoarthritis Outcome Score (KOOS) surveys. Cytokine and growth factor concentrations in whole blood and APS were measured using enzyme-linked immunosorbent assays. Statistical analyses were used to identify relationships between OA patient metrics and cytokines. The results of this study indicated that anti-inflammatory cytokines were preferentially increased compared to inflammatory cytokines in APS from 98% of OA patients. APS contained high concentrations of anti-inflammatory proteins including 39,000 ± 20,000 pg/ml IL-1ra, 21,000 ± 5,000 pg/ml sIL-1RII, 2,100 ± 570 pg/ml sTNF-RI, and 4,200 ± 1,500 pg/ml sTNF-RII. Analysis of the 82 patient metrics indicated that no single patient metric was strongly correlated (R2 > .7) with the key cytokine concentrations in APS. Therefore, APS can be prepared from a broad range of OA patients. PMID:24981198

Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations

PubMed Central

Huybrechts, Krista F.; Hernández-Díaz, Sonia; Patorno, Elisabetta; Desai, Rishi J.; Mogun, Helen; Dejene, Sara Z.; Cohen, Jacqueline M.; Panchaud, Alice; Cohen, Lee; Bateman, Brian T.

2017-01-01

IMPORTANCE The frequency of antipsychotic (AP) use during pregnancy has approximately doubled during the last decade. However, little is known about their safety for the developing fetus, and concerns have been raised about a potential association with congenital malformations. OBJECTIVE To examine the risk for congenital malformations overall and cardiac malformations associated with first-trimester exposure to APs. DESIGN, SETTING, AND PARTICIPANTS This nationwide sample of 1 360 101 pregnant women enrolled in Medicaid with a live-born infant constituted the pregnancy cohort nested in the Medicaid Analytic Extract database, which included data from January 1, 2000, to December 31, 2010. Participants were enrolled in Medicaid from 3 months before their last menstrual period through at least 1 month after delivery. Relative risks (RRs) were estimated using generalized linear models with fine stratification on the propensity score to control for the underlying psychiatric disorders and other potential confounders. Data were analyzed during 2015. EXPOSURES Use of APs during the first trimester, the etiologically relevant period for organogenesis. MAIN OUTCOMES AND MEASURES Major congenital malformations overall and cardiac malformations identified during the first 90 days after delivery. RESULTS Of the 1 341 715 pregnancies that met inclusion criteria (mean [SD] age of women, 24.02 [5.77] years), 9258 (0.69%) filled at least 1 prescription for an atypical AP and 733 (0.05%) filled at least 1 prescription for a typical AP during the first trimester. Overall, 32.7 (95% CI, 32.4–33.0) per 1000 births not exposed to APs were diagnosed with congenital malformations compared with 44.5 (95% CI, 40.5–48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6–54.7) per 1000 births exposed to typical APs. Unadjusted analyses suggested an increased risk for malformations overall for atypical APs (RR, 1.36; 95% CI, 1.24–1.50) but not for typical APs (RR, 1.17; 95% CI, 0.81–1.68). After confounding adjustment, the RR was reduced to 1.05 (95% CI, 0.96–1.16) for atypical APs and 0.90 (95% CI, 0.62–1.31) for typical APs. The findings for cardiac malformations were similar. For the individual agents examined, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02–1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88–1.81) was found for risperidone that was independent of measured confounders. CONCLUSIONS AND RELEVANCE Evidence from this large study suggests that use of APs early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study. PMID:27540849

Effect of baroreceptor denervation on the autonomic control of arterial pressure in conscious mice.

PubMed

Rodrigues, Fernanda Luciano; de Oliveira, Mauro; Salgado, Helio Cesar; Fazan, Rubens

2011-09-01

This study evaluated the role of arterial baroreceptors in arterial pressure (AP) and pulse interval (PI) regulation in conscious C57BL mice. Male animals, implanted with catheters in a femoral artery and a jugular vein, were submitted to sino-aortic (SAD), aortic (Ao-X) or carotid sinus denervation (Ca-X), 5 days prior to the experiments. After basal recording of AP, the lack of reflex bradycardia elicited by administration of phenylephrine was used to confirm the efficacy of SAD, and cardiac autonomic blockade with methylatropine and propranolol was performed. The AP and PI variability were calculated in the time and frequency domains (spectral analysis/fast Fourier transform) with the spectra quantified in low- (LF; 0.25-1 Hz) and high-frequency bands (HF; 1-5 Hz). Basal AP and AP variability were higher after SAD, Ao-X or Ca-X than in intact mice. Pulse interval was similar among the groups, whereas PI variability was lower after SAD. Atropine elicited a slight tachycardia in control mice but did not change PI after total or partial denervation. The bradycardia caused by propranolol was higher after SAD, Ao-X or Ca-X compared with intact mice. The increase in the variability of AP was accompanied by a marked increase in the LF and HF power of the AP spectra after baroreceptor denervation. The LF and HF power of the PI were reduced by SAD and by Ao-X or Ca-X. Therefore, both sino-aortic and partial baroreceptor denervation in mice elicits hypertension and a remarkable increase in AP variability and cardiac sympathetic tonus. Spectral analysis showed an important contribution of the baroreflex in the power of LF oscillations of the PI spectra. Both sets of baroreceptors seem to be equally important in the autonomic regulation of the cardiovascular system in mice.

Toward on-chip, in-cell recordings from cultured cardiomyocytes by arrays of gold mushroom-shaped microelectrodes

PubMed Central

Fendyur, Anna; Spira, Micha E.

2012-01-01

Cardiological research greatly rely on the use of cultured primary cardiomyocytes (CMs). The prime methodology to assess CM network electrophysiology is based on the use of extracellular recordings by substrate-integrated planar Micro-Electrode Arrays (MEAs). Whereas this methodology permits simultaneous, long-term monitoring of the CM electrical activity, it limits the information to extracellular field potentials (FPs). The alternative method of intracellular action potentials (APs) recordings by sharp- or patch-microelectrodes is limited to a single cell at a time. Here, we began to merge the advantages of planar MEA and intracellular microelectrodes. To that end we cultured rat CM on micrometer size protruding gold mushroom-shaped microelectrode (gMμEs) arrays. Cultured CMs engulf the gMμE permitting FPs recordings from individual cells. Local electroporation of a CM converts the extracellular recording configuration to attenuated intracellular APs with shape and duration similar to those recorded intracellularly. The procedure enables to simultaneously record APs from an unlimited number of CMs. The electroporated membrane spontaneously recovers. This allows for repeated recordings from the same CM a number of times (>8) for over 10 days. The further development of CM-gMμE configuration opens up new venues for basic and applied biomedical research. PMID:22936913

Is Self-Regulation "All in the family"? Testing Environmental Effects using Within-Family Quasi-Experiments.

PubMed

Deater-Deckard, Kirby

2016-05-01

Most of the individual difference variance in the population is found within families, yet studying the processes causing this variation is difficult due to confounds between genetic and nongenetic influences. Quasi-experiments can be used to test hypotheses regarding environment exposure (e.g., timing, duration) while controlling for genetic confounds. To illustrate, two studies of cognitive self-regulation in childhood (i.e., working memory [WM], effortful control [EC], attention span/persistence [A/P]) are presented. Study 1 utilized an identical twin differences design ( N = 85 to 98 pairs) to control for genetic differences while using relative twin birth weight difference to predict relative twin difference in WM and EC. Larger relative twin difference in WM and EF was predicted by the combination of shorter gestation and larger relative birth weight difference. Study 2 utilized an adoptive sibling relative difference design ( N = 123 same-sex pairs) to control for genetic similarity while using relative sibling difference in the age at time of adoption to predict relative sibling difference in A/P. Larger relative sibling difference in A/P was predicted by the combination of larger relative difference in time in the adoptive home and age at adoption. Within-family quasi-experimental designs allow stronger inferences about hypothesized environmental influences than between-family designs permit.

External defibrillation in the left lateral position--a comparison of manual paddles with self-adhesive pads.

PubMed

Dodd, Tamsin E L; Deakin, Charles D; Petley, Graham W; Clewlow, Frank

2004-12-01

Firm paddle force during defibrillation lowers transthoracic impedance (TTI) and increases transmyocardial current, increasing the chances of successful cardioversion. Current protocols recommend that if defibrillation using the anterior-apical (AA) paddle position fails, the anterior-posterior (AP) position should be used. This generally requires the patient to be placed in the left lateral position with the operator leaning over the patient. Avoiding physical contact with the patient during defibrillation subjectively makes application of firm paddle force difficult in the AP position. We compared TTI between the AA and AP positions and between manual paddles and self-adhesive pads to establish if the AP position precludes firm paddle force and to compare TTI between paddles and self-adhesive pads. Twenty-one consecutive patients undergoing elective cardioversion (age 39-82) were studied. TTI was measured between pairs of manually held paddles and self-adhesive pads using AA placement with the patient supine, and AP placement with the patient left lateral position. Mean TTI using the AP electrode position was lower using manual paddles (66.5 Omega; 95% CI 60.2-72.9 Omega) than that using self-adhesive pads (92.1 Omega; 95% CI 81.5-102.7 Omega; 95% CI between the mean =15.8-35.5 Omega; P <0.0001). TTI was significantly less using the manual paddles compared with self-adhesive pads in both AA and AP positions (P <0.0001). Despite the subjective difficulties of defibrillating patients in the AP position whilst leaning over them, use of manual paddles achieves a lower TTI than that achieved with self-adhesive pads.

Enigma interacts with adaptor protein with PH and SH2 domains to control insulin-induced actin cytoskeleton remodeling and glucose transporter 4 translocation.

PubMed

Barrès, Romain; Grémeaux, Thierry; Gual, Philippe; Gonzalez, Teresa; Gugenheim, Jean; Tran, Albert; Le Marchand-Brustel, Yannick; Tanti, Jean-François

2006-11-01

APS (adaptor protein with PH and SH2 domains) initiates a phosphatidylinositol 3-kinase-independent pathway involved in insulin-stimulated glucose transport. We recently identified Enigma, a PDZ and LIM domain-containing protein, as a partner of APS and showed that APS-Enigma complex plays a critical role in actin cytoskeleton organization in fibroblastic cells. Because actin rearrangement is important for insulin-induced glucose transporter 4 (Glut 4) translocation, we studied the potential involvement of Enigma in insulin-induced glucose transport in 3T3-L1 adipocytes. Enigma mRNA was expressed in differentiated adipocytes and APS and Enigma were colocalized with cortical actin. Expression of an APS mutant unable to bind Enigma increased the insulin-induced Glut 4 translocation to the plasma membrane. By contrast, overexpression of Enigma inhibited insulin-stimulated glucose transport and Glut 4 translocation without alterations in proximal insulin signaling. This inhibitory effect was prevented with the deletion of the LIM domains of Enigma. Using time-lapse fluorescent microscopy of green fluorescent protein-actin, we demonstrated that the overexpression of Enigma altered insulin-induced actin rearrangements, whereas the expression of Enigma without its LIM domains was without effect. A physiological link between increased expression of Enigma and an alteration in insulin-induced glucose uptake was suggested by the increase in Enigma mRNA expression in adipose tissue of diabetic obese patients. Taken together, these data strongly suggest that the interaction between APS and Enigma is involved in insulin-induced Glut 4 translocation by regulating cortical actin remodeling and raise the possibility that modification of APS/Enigma ratio could participate in the alteration of insulin-induced glucose uptake in adipose tissue.

Dynamic Action Potential Restitution Contributes to Mechanical Restitution in Right Ventricular Myocytes From Pulmonary Hypertensive Rats.

PubMed

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.

The Futility of Propensity Score Methods in a Statewide Study of International Baccalaureate (IB)

ERIC Educational Resources Information Center

May, Henry; Rodriguez, Awilda; Sirinides, Philip M.; Perna, Laura W.; Yee, April; Ransom, Tafaya

2014-01-01

With the goal of increasing students' academic readiness for college, high schools in the United States are increasingly offering "credit-based transition programs," including International Baccalaureate (IB), Advanced Placement (AP), and dual enrollment. Existing research points to the promise of IB, AP, and other credit-based…

Melatonin potentiates tear secretion induced by diadenosine tetraphosphate in the rabbit.

PubMed

Hoyle, Charles H V; Peral, Assumpta; Pintor, Jesús

2006-12-15

Diadenosine tetraphosphate (Ap(4)A, 0.03 nmol) applied topically to the cornea of New Zealand white rabbits, evoked an increase in tear secretion of 9.7 +/- 2.60% (N=7). Melatonin (1 nmol) had no significant effect. Application of Ap(4)A in combination with melatonin, evoked a significantly greater increase in tear secretion of 34.2 +/- 5.8% (N=11). This potentiating effect of melatonin was blocked by pretreating the cornea with a topical application of the melatonin receptor antagonist, luzindole (240 nmol). Melatonin combined with Ap(4)A may be useful for treating dry eye conditions.

Development of recombinant cell line co-expressing mutated Nav1.5, Kir2.1, and hERG for the safety assay of drug candidates.

PubMed

Fujii, Masato; Ohya, Susumu; Yamamura, Hisao; Imaizumi, Yuji

2012-07-01

To provide a high-throughput screening method for human ether-a-go-go-gene-related gene (hERG) K(+) channel inhibition, a new recombinant cell line, in which single action potential (AP)-induced cell death was produced by gene transfection. Mutated human cardiac Na(+) channel Nav1.5 (IFM/Q3), which shows extremely slow inactivation, and wild-type inward rectifier K(+) channel, Kir2.1, were stably co-expressed in HEK293 cells (IFM/Q3+Kir2.1). In IFM/Q3+Kir2.1, application of single electrical stimulation (ES) elicited a long AP lasting more than 30 s and led cells to die by more than 70%, whereas HEK293 co-transfected with wild-type Nav1.5 and Kir2.1 fully survived. The additional expression of hERG K(+) channels in IFM/Q3+Kir2.1 shortened the duration of evoked AP and thereby markedly reduced the cell death. The treatment of the cells with hERG channel inhibitors such as nifekalant, E-4031, cisapride, terfenadine, and verapamil, recovered the prolonged AP and dose-dependently facilitated cell death upon ES. The EC(50) values to induce the cell death were 3 µM, 19 nM, 17 nM, 74 nM, and 3 µM, respectively, whereas 10 µM nifedipine did not induce cell death. Results indicate the high utility of this cell system for hERG K(+) channel safety assay.

Astragalus polysaccharide suppresses palmitate-induced apoptosis in human cardiac myocytes: the role of Nrf1 and antioxidant response

PubMed Central

Zhang, Ji; Gu, Jian-Yun; Chen, Zhi-Song; Xing, Kai-Chen; Sun, Bing

2015-01-01

Objective: Previous studies have shown that Astragalus polysaccharides (APS) can be used to ameliorate cardiotoxicity due to chemotherapy and improve the cardiac function. However, the mechanism by which APS mediate this effect is unclear. In the present study, the effects of APS, which suppressed ROS-mediated apoptosis through Nrf1 accumulation in human cardiac myocytes (HCMs), was investigated. Methods: The cell viability was detected by the CCK8 assay. The cell apoptosis was assessed by annexin V-PI double-labeling staining. Expression of genes and proteins were analyzed by real-time PCR and western blotting respectively. Nrf1 gene was overexpressed using a lentiviral expression vector in HCMs in vitro, in order to explore the mechanism by which the Nrf1 promoted cell growth. Results: CCK8 and Annexin V-PI double-labeling showed that PAL induced cell death in a concentration-dependent manner, and suppressed HCMs proliferation. The combination PAL with APS was significantly decreased the percentage of the early phase of apoptosis cells. ROS levels were increased in HCMs by exposure to PAL. APS treatment significantly inhibited generation of ROS in response to palmitate. Moreover, PAL administration significantly decreased the mRNA and proteins expression of Bcl-2 as well as increased the mRNA expression of BAX and the protein expression of caspase-3 and caspase-8 as compare to those of control group, but APS treatment could reverse PA-induced HCMs apoptosis. The levels of reactive oxygen species (ROS), which was an oxidative stress marker, was significantly increased in cardiomyocytes by exposure to PAL, but overexpressing Nrf1 could ameliorate ROS-induced cardiomyocyte toxicity and increase the expression of SOD1 and SOD2 in HCMs by overexpressing Nrf1. Conclusions: This study demonstrated that the PAL could induce HCMs apoptosis. However, APS could reverse PAL-induced cardiomyocyte toxicity, at least partially, through suppression ROS and Nrf1 accumulation in HCMs. PMID:26045757

Astragalus polysaccharide suppresses palmitate-induced apoptosis in human cardiac myocytes: the role of Nrf1 and antioxidant response.

PubMed

Zhang, Ji; Gu, Jian-Yun; Chen, Zhi-Song; Xing, Kai-Chen; Sun, Bing

2015-01-01

Previous studies have shown that Astragalus polysaccharides (APS) can be used to ameliorate cardiotoxicity due to chemotherapy and improve the cardiac function. However, the mechanism by which APS mediate this effect is unclear. In the present study, the effects of APS, which suppressed ROS-mediated apoptosis through Nrf1 accumulation in human cardiac myocytes (HCMs), was investigated. The cell viability was detected by the CCK8 assay. The cell apoptosis was assessed by annexin V-PI double-labeling staining. Expression of genes and proteins were analyzed by real-time PCR and western blotting respectively. Nrf1 gene was overexpressed using a lentiviral expression vector in HCMs in vitro, in order to explore the mechanism by which the Nrf1 promoted cell growth. CCK8 and Annexin V-PI double-labeling showed that PAL induced cell death in a concentration-dependent manner, and suppressed HCMs proliferation. The combination PAL with APS was significantly decreased the percentage of the early phase of apoptosis cells. ROS levels were increased in HCMs by exposure to PAL. APS treatment significantly inhibited generation of ROS in response to palmitate. Moreover, PAL administration significantly decreased the mRNA and proteins expression of Bcl-2 as well as increased the mRNA expression of BAX and the protein expression of caspase-3 and caspase-8 as compare to those of control group, but APS treatment could reverse PA-induced HCMs apoptosis. The levels of reactive oxygen species (ROS), which was an oxidative stress marker, was significantly increased in cardiomyocytes by exposure to PAL, but overexpressing Nrf1 could ameliorate ROS-induced cardiomyocyte toxicity and increase the expression of SOD1 and SOD2 in HCMs by overexpressing Nrf1. This study demonstrated that the PAL could induce HCMs apoptosis. However, APS could reverse PAL-induced cardiomyocyte toxicity, at least partially, through suppression ROS and Nrf1 accumulation in HCMs.

[Spatial variation of soil phosphorus in flooded area of the Yellow River based on GIS and geo-statistical methods: A case study in Zhoukou City, Henan, China.

PubMed

Jia, Zhen Yu; Zhang, Jun Hua; Ding, Sheng Yan; Feng, Shu; Xiong, Xiao Bo; Liang, Guo Fu

2016-04-22

Soil phosphorus is an important indicator to measure the soil fertility, because the content of soil phosphorus has an important effect on physical and chemical properties of soil, plant growth, and microbial activity in soil. In this study, the soil samples collecting and indoor analysis were conducted in Zhoukou City located in the flooded area of the Yellow River. By using GIS combined with geo-statistics, we tried to analyze the spatial variability and content distribution of soil total phosphorus (TP) and soil available phosphorus (AP) in the study area. Results showed that TP and AP of both soil layers (0-20 cm and 20-40 cm) were rich, and the contents of TP and AP in surface layer (0-20 cm) were higher than in the second layer (20-40 cm). TP and AP of both soil layers exhibited variation at medium level, and AP had varied much higher than TP. TP of both layers showed medium degree of anisotropy which could be well modeled by the Gaussian model. TP in the surface layer showed strong spatial correlation, but that of the second layer had medium spatial correlation. AP of both layers had a weaker scope in anisotropy which could be simulated by linear model, and both soil layers showed weaker spatial correlations. TP of both soil layers showed a slowly rising change from southwest to northeast of the study area, while it gradually declined from northwest to southeast. AP in soil surface layer exhibited an increase tendency firstly and then decrease from southwest to the northeast, while it decreased firstly and then increased from southeast to the northwest. AP in the second soil layer had an opposite change in the southwest to the northeast, while it showed continuously increasing tendency from northwest to the southeast. The contents of TP and AP in the surface layer presented high grades and the second layer of TP belonged to medium grade, but the second layer of AP was in a lower grade. The artificial factors such as land use type, cropping system, irrigation and fertilization were the main factors influencing the distribution and spatial variation of soil phosphorus in this area.

Compartment-specific control of signaling from a DNA-sensing immune receptor.

PubMed

Engel, Alex; Barton, Gregory M

2010-11-30

Many cell signaling events are spatially organized, enabling control of specificity, amplitude, and duration. Toll-like receptor 9 (TLR9) binds to nucleic acid sequences present in bacteria or DNA viruses and initiates a signaling pathway that culminates in the transcriptional induction of genes important for host defense, such as those encoding proinflammatory cytokines and type I interferon. A specialized membrane trafficking pathway has been described that is required for a specific branch of TLR9 signaling: the production of type I interferon. Cells deficient for the clathrin adaptor complex AP-3 failed to traffic TLR9 to a specific endosomal compartment and were unable to produce type I interferon despite normal increases in the abundance of interleukin-12p40, a proinflammatory cytokine. These findings support a model in which the targets of TLR9 engagement are controlled by the compartment in which TLR9 is activated.

Microparticle and mitochondrial release during extended storage of different types of platelet concentrates.

PubMed

Marcoux, Geneviève; Duchez, Anne-Claire; Rousseau, Matthieu; Lévesque, Tania; Boudreau, Luc H; Thibault, Louis; Boilard, Eric

2017-05-01

On activation, platelets release vesicles called microparticles (MPs). MPs are heterogeneous with regard to the presence or absence of mitochondria. We quantified MPs in platelet concentrates (PCs) taking their mitochondrial content into account. Platelet-rich plasma (PRP), buffy coat (BC) and apheresis (AP) PCs were tested through 7 days of storage. A combination of flow cytometry and spanning-tree progression analysis of density-normalized events (SPADE) was used to determine MP and mitochondrial release during storage. All the PC biochemical parameters complied with transfusion standards at all times. Platelet activation markers increased during storage and were higher for PRP than other types of PCs. Concentrations of MPs and extracellular mitochondria interpreted by SPADE algorithm were significantly higher in PRP than other in PCs and were stable throughout storage. The mode of preparation, rather than storage duration, impacts the release of MPs and mitochondria in PCs.

BDNF mRNA abundance regulated by antidromic action potentials and AP-LTD in hippocampus.

PubMed

Bukalo, Olena; Lee, Philip R; Fields, R Douglas

2016-12-02

Action-potential-induced LTD (AP-LTD) is a form of synaptic plasticity that reduces synaptic strength in CA1 hippocampal neurons firing antidromically during sharp-wave ripples. This firing occurs during slow-wave sleep and quiet moments of wakefulness, which are periods of offline replay of neural sequences learned during encoding sensory information. Here we report that rapid and persistent down-regulation of different mRNA transcripts of the BDNF gene accompanies AP-LTD, and that AP-LTD is abolished in mice with the BDNF gene knocked out in CA1 hippocampal neurons. These findings increase understanding of the mechanism of AP-LTD and the cellular mechanisms of memory consolidation. Published by Elsevier Ireland Ltd.

Use of the VIP-Man model to calculate energy imparted and effective dose for x-ray examinations.

PubMed

Winslow, Mark; Huda, Walter; Xu, X George; Chao, T C; Shi, C Y; Ogden, Kent M; Scalzetti, Ernest M

2004-02-01

A male human tomographic model was used to calculate values of energy imparted (epsilon) and effective dose (E) for monoenergetic photons (30-150 keV) in radiographic examinations. Energy deposition in the organs and tissues of the human phantom were obtained using Monte Carlo simulations. Values of E/epsilon were obtained for three common projections [anterior-posterior (AP), posterior-anterior (PA), and lateral (LAT)] of the head, cervical spine, chest, and abdomen, respectively. For head radiographs, all three projections yielded similar E/epsilon values. At 30 keV, the value of E/epsilon was approximately 1.6 mSv J(-1), which is increased to approximately 7 mSv J(-1) for 150 keV photons. The AP cervical spine was the only projection investigated where the value of E/epsilon decreased with increasing photon energy. Above 70 keV, cervical spine E/epsilon values showed little energy dependence and ranged between approximately 8.5 mSv J(-1) for PA projections and approximately 17 mSv J(-1) for AP projections. The values of E/epsilon for AP chest examinations showed very little variation with photon energy, and had values of approximately 23 mSv J(-1). Values of E/epsilon for PA and LAT chest projections were substantially lower than the AP projections and increased with increasing photon energy. For abdominal radiographs, differences between the PA and LAT projections were very small. All abdomen projections showed an increase in the E/epsilon ratio with increasing photon energy, and reached a maximum value of approximately 13.5 mSv J(-1) for AP projections, and approximately 9.5 mSv J(-1) for PA/lateral projections. These monoenergetic E/epsilon values can generate values of E/epsilon for any x-ray spectrum, and can be used to convert values of energy imparted into effective dose for patients undergoing common head and body radiological examinations.

Absolute pitch memory: its prevalence among musicians and dependence on the testing context.

PubMed

Wong, Yetta Kwailing; Wong, Alan C-N

2014-04-01

Absolute pitch (AP) is widely believed to be a rare ability possessed by only a small group of gifted and special individuals (AP possessors). While AP has fascinated psychologists, neuroscientists, and musicians for more than a century, no theory can satisfactorily explain why this ability is so rare and difficult to learn. Here, we show that AP ability appears rare because of the methodological issues of the standard pitch-naming test. Specifically, the standard test unnecessarily poses a high decisional demand on AP judgments and uses a testing context that is highly inconsistent with one's musical training. These extra cognitive challenges are not central to AP memory per se and have thus led to consistent underestimation of AP ability in the population. Using the standard test, we replicated the typical findings that the accuracy for general violinists was low (12.38 %; chance level = 0 %). With identical stimuli, scoring criteria, and participants, violinists attained 25 % accuracy in a pitch verification test in which the decisional demand of AP judgment was reduced. When the testing context was increasingly similar to their musical experience, verification accuracy improved further and reached 39 %, three times higher than that for the standard test. Results were replicated with a separate group of pianists. Our findings challenge current theories about AP and suggest that the prevalence of AP among musicians has been highly underestimated in prior work. A multimodal framework is proposed to better explain AP memory.

Geomagnetic storms can trigger stroke: evidence from 6 large population-based studies in Europe and Australasia.

PubMed

Feigin, Valery L; Parmar, Priya G; Barker-Collo, Suzanne; Bennett, Derrick A; Anderson, Craig S; Thrift, Amanda G; Stegmayr, Birgitta; Rothwell, Peter M; Giroud, Maurice; Bejot, Yannick; Carvil, Phillip; Krishnamurthi, Rita; Kasabov, Nikola

2014-06-01

Although the research linking cardiovascular disorders to geomagnetic activity is accumulating, robust evidence for the impact of geomagnetic activity on stroke occurrence is limited and controversial. We used a time-stratified case-crossover study design to analyze individual participant and daily geomagnetic activity (as measured by Ap Index) data from several large population-based stroke incidence studies (with information on 11 453 patients with stroke collected during 16 031 764 person-years of observation) in New Zealand, Australia, United Kingdom, France, and Sweden conducted between 1981 and 2004. Hazard ratios and corresponding 95% confidence intervals (CIs) were calculated. Overall, geomagnetic storms (Ap Index 60+) were associated with 19% increase in the risk of stroke occurrence (95% CI, 11%-27%). The triggering effect of geomagnetic storms was most evident across the combined group of all strokes in those aged <65 years, increasing stroke risk by >50%: moderate geomagnetic storms (60-99 Ap Index) were associated with a 27% (95% CI, 8%-48%) increased risk of stroke occurrence, strong geomagnetic storms (100-149 Ap Index) with a 52% (95% CI, 19%-92%) increased risk, and severe/extreme geomagnetic storms (Ap Index 150+) with a 52% (95% CI, 19%-94%) increased risk (test for trend, P<2×10(-16)). Geomagnetic storms are associated with increased risk of stroke and should be considered along with other established risk factors. Our findings provide a framework to advance stroke prevention through future investigation of the contribution of geomagnetic factors to the risk of stroke occurrence and pathogenesis. © 2014 American Heart Association, Inc.

Heavy Smoking Is Associated With Lower Age at First Episode of Acute Pancreatitis and a Higher Risk of Recurrence.

PubMed

Munigala, Satish; Conwell, Darwin L; Gelrud, Andres; Agarwal, Banke

2015-08-01

There is limited data on cigarette smoking and the risk of acute pancreatitis (AP). We evaluated the influence of cigarette smoking on AP risk and clinical presentation in a large cohort of Veteran's Administration (VA) patients. Retrospective study of VA patients from 1998 to 2007. Exclusion criteria included (1) history of chronic pancreatitis (n = 3222) or gallstones (n = 14,574) and (2) age younger than 15 years (n = 270). A 2-year washout period was used to exclude patients with pre-existing recurrent AP. The study included 484,624 patients. From 2001 to 2007, a total of 6799 (1.4%) patients had AP. Alcohol (risk ratio, 4.20) and smoking (risk ratio, 1.78) were independent significant risk factors of AP on multiple regression analysis. Smoking increased the risk of AP in both nonalcoholics (0.57% vs 1.1%) and alcoholics (2.6% vs 4.1%). Smoking was associated with younger mean age at first episode of AP and higher likelihood of recurrent AP (≥4 episodes) in both nonalcoholics and alcoholics. The interval between recurrent episodes was not altered by alcohol or smoking. In a large cohort of VA patients, smoking is an independent risk factor for AP and augmented the effect of alcohol on the risk, age of onset, and recurrence of AP.

Alkaline Phosphatase-Positive Immortal Mouse Embryo Fibroblasts Are Cells in a Transitional Reprogramming State Induced to Face Environmental Stresses

PubMed Central

Evangelista, Monica; Baroudi, Mariama El; Rizzo, Milena; Tuccoli, Andrea; Poliseno, Laura; Pellegrini, Marco; Rainaldi, Giuseppe

2015-01-01

In this study, we report that immortal mouse embryonic fibroblasts (I-MEFs) have a baseline level of cells positive for alkaline phosphatase (AP+) staining. Environmental stresses, including long-lasting growth in the absence of expansion and treatment with drugs, enhance the frequency of AP+ I-MEFs. By adapting fast red AP staining to the sorting procedure, we separated AP+ and AP− I-MEFs and demonstrated that the differentially expressed genes are consistent with a reprogrammed phenotype. In particular, we found that sestrin 1 is upregulated in AP+ I-MEFs. We focused on this gene and demonstrated that increased sestrin 1 expression is accompanied by the growth of I-MEFs in the absence of expansion and occurs before the formation of AP+ I-MEFs. Together with sestrin 1 upregulation, we found that AP+ I-MEFs accumulated in the G1 phase of the cell cycle, suggesting that the two events are causally related. Accordingly, we found that silencing sestrin 1 expression reduced the frequency and G1 accumulation of AP+ I-MEFs. Taken together, our data suggested that I-MEFs stressed by environmental changes acquire the AP+ phenotype and achieve a quiescent state characterized by a new transcriptional network. PMID:26740745

Calsequestrin mutation and catecholaminergic polymorphic ventricular tachycardia: a simulation study of cellular mechanism.

PubMed

Faber, Gregory M; Rudy, Yoram

2007-07-01

Patients with a missense mutation of the calsequestrin 2 gene (CASQ2) are at risk for catecholaminergic polymorphic ventricular tachycardia. This mutation (CASQ2(D307H)) results in decreased ability of CASQ2 to bind Ca2+ in the sarcoplasmic reticulum (SR). In this theoretical study, we investigate a potential mechanism by which CASQ2(D307H) manifests its pro-arrhythmic consequences in patients. Using simulations in a model of the guinea pig ventricular myocyte, we investigate the mutation's effect on SR Ca2+ storage, the Ca2+ transient (CaT), and its indirect effect on ionic currents and membrane potential. We model the effects of isoproterenol (ISO) on Ca(V)1.2 (the L-type Ca2+ current, I(Ca(L))) and other targets of beta-adrenergic stimulation. ISO increases I(Ca(L)), prolonging action potential (AP) duration (Control: 172 ms, +ISO: 207 ms, at cycle length of 1500 ms) and increasing CaT (Control: 0.79 microM, +ISO: 1.61 microM). ISO increases I(Ca(L)) by reducing the fraction of channels which undergo voltage-dependent inactivation and increasing transitions from a non-conducting to conducting mode of channel gating. CASQ2(D307H) reduces SR storage capacity, thereby reducing the magnitude of CaT (Control: 0.79 microM, CASQ2(D307H): 0.52 microM, at cycle length of 1500 ms). The combined effect of CASQ2(D307H) and ISO elevates SR free Ca2+ at a rapid rate, leading to store-overload-induced Ca2+ release and delayed afterdepolarization (DAD). If resting membrane potential is sufficiently elevated, the Na+-Ca2+ exchange-driven DAD can trigger I(Na) and I(Ca(L)) activation, generating a triggered arrhythmogenic AP. The CASQ2(D307H) mutation manifests its pro-arrhythmic consequences due to store-overload-induced Ca2+ release and DAD formation due to excess free SR Ca2+ following rapid pacing and beta-adrenergic stimulation.

The effect of the Advanced Placement Training and Incentive Program on increasing enrollment and performance on Advanced Placement science exams

NASA Astrophysics Data System (ADS)

Ramsey, Susan Brady

The purpose of this study is to examine the effectiveness of the National Math and Science Initiative's Advanced Placement Training and Incentive Program (APTIP) on the number of students taking AP science courses and their performance. The study evaluated 39 schools over a six-year period in six states that participate in the APTIP. The National Math and Science Initiative provided data for cohort I. A general linear model for repeated measures was used to evaluate the data. Data was evaluated three years prior to the intervention and three years during the intervention, which will actually continue for two more years (2012 and 2013) since cohort I schools were awarded five years of support. Students in APTIP schools enrolled in more AP science exams (AP Biology, AP Chemistry, AP Environmental Science, and AP Physics-B) over the course of the intervention. The quantity of students earning qualifying scores increased during the intervention years. APTIP is a multi-tiered program that includes seven days of teacher training, three six-hour student prep sessions, school equipment, reduced exam fees, and monetary incentives for students and teachers. This program positively impacted the quantity of enrollment and qualifying scores during the three years evaluated in this study. Increases in the number of female and African American students' test takers their and qualifying scores were seen in all three years of the APTIP intervention. This study supports the premise that the first step to increasing the Science, technology, engineering, and math (STEM) pipeline is giving access to advanced courses to more students in high schools.

Apple Polyphenol Suppresses Indomethacin-Induced Gastric Damage in Experimental Animals by Lowering Oxidative Stress Status and Modulating the MAPK Signaling Pathway.

PubMed

Lee, Yi-Chen; Cheng, Chun-Wen; Lee, Huei-Jane; Chu, Huei-Chuien

2017-11-01

Indomethacin is a nonsteroid anti-inflammatory drug (NSAID) that is used to alleviate pain and inflammation in clinical medicine. Previous studies indicated that NSAIDs can cause gastrointestinal mucosal complications, and it is associated with mucosal lipid peroxidation and oxidative damage. Based on the evidences, decreasing oxidative stress may be an ideal therapeutic strategy for preventing gastrointestinal ulcer. Apple (Rosaceae Malus sp.) is one of the most commonly consumed fruits worldwide. The abundant polyphenolic constituents have received increasing attention for decades. In both in vivo and in vitro studies, the reports showed that apple polyphenol (AP) seems to provide an indirect antioxidant protection by activating cellular antioxidant enzymes to defend against oxidative stress. To address this issue and develop AP into a healthy improvement supplement, we studied the effect and potential mechanisms of AP in indomethacin-treated animal. The results showed AP can decelerate the gastric lesion, significantly suppress lipid peroxidation, increase the level of glutathione and the activity of catalase, and regulate the MAPK signaling proteins. These findings imply that AP protects the gastric mucosa from indomethacin-caused lesions and the protection is at least partially attributable to its antioxidative properties. This alternative medical function of AP may be a safe and effective intervention for preventing indomethacin-induced gastric complications.

Supplementation with Astragalus polysaccharides alters Aeromonas-induced tissue-specific cellular immune response.

PubMed

Abuelsaad, Abdelaziz S A

2014-01-01

Members of the genus Aeromonas inhabit various aquatic environments and are responsible for a number of intestinal and extra-intestinal infections in humans as well as other animals. Astragalus species are used in Chinese traditional medicine as antiperspirant, antihypertensive, diuretic and tonic treatments and have been used for treatment of patients with leukemia and uterine cancers. The present study was aimed to investigate immunomodulatory effect of Astragalus polysaccharides (APS) treatment on Aeromonas hydrophila-infected mice. The present data showed that APS-treatment ameliorated neutrophils phagocytic activity and reactive oxygen species (ROS) production in intestinal tissues of infected mice. Moreover, APS treatment induced a highly significantly (P < 0.001) increase in the number of CD4(+) T cells in the intestinal tissues and thymus, however, number of CD4(+) T cells in the spleens of infected mice not significantly changed with APS treatment. On the other hand, APS-treatment caused a very highly significant (P < 0.001) decrease in the number of CD8(+) T cells in the spleens and thymus of infected mice. In conclusion, the present data suggested that APS treatment reduced ROS production, downmodulated neutrophils activity, and increased CD4(+)/CD8(+) T cells ratio in A. hydrophila-infected mice. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Adaptor Protein CD2AP Is a Coordinator of Neurotrophin Signaling-Mediated Axon Arbor Plasticity

PubMed Central

Harrison, Benjamin J.; Venkat, Gayathri; Lamb, James L.; Hutson, Tom H.; Drury, Cassa; Rau, Kristofer K.; Bunge, Mary Barlett; Mendell, Lorne M.; Gage, Fred H.; Johnson, Richard D.; Hill, Caitlin E.; Rouchka, Eric C.; Moon, Lawrence D.F.

2016-01-01

Growth of intact axons of noninjured neurons, often termed collateral sprouting, contributes to both adaptive and pathological plasticity in the adult nervous system, but the intracellular factors controlling this growth are largely unknown. An automated functional assay of genes regulated in sensory neurons from the rat in vivo spared dermatome model of collateral sprouting identified the adaptor protein CD2-associated protein (CD2AP; human CMS) as a positive regulator of axon growth. In non-neuronal cells, CD2AP, like other adaptor proteins, functions to selectively control the spatial/temporal assembly of multiprotein complexes that transmit intracellular signals. Although CD2AP polymorphisms are associated with increased risk of late-onset Alzheimer's disease, its role in axon growth is unknown. Assessments of neurite arbor structure in vitro revealed CD2AP overexpression, and siRNA-mediated knockdown, modulated (1) neurite length, (2) neurite complexity, and (3) growth cone filopodia number, in accordance with CD2AP expression levels. We show, for the first time, that CD2AP forms a novel multiprotein complex with the NGF receptor TrkA and the PI3K regulatory subunit p85, with the degree of TrkA:p85 association positively regulated by CD2AP levels. CD2AP also regulates NGF signaling through AKT, but not ERK, and regulates long-range signaling though TrkA+/RAB5+ signaling endosomes. CD2AP mRNA and protein levels were increased in neurons during collateral sprouting but decreased following injury, suggesting that, although typically considered together, these two adult axonal growth processes are fundamentally different. These data position CD2AP as a major intracellular signaling molecule coordinating NGF signaling to regulate collateral sprouting and structural plasticity of intact adult axons. SIGNIFICANCE STATEMENT Growth of noninjured axons in the adult nervous system contributes to adaptive and maladaptive plasticity, and dysfunction of this process may contribute to neurologic pathologies. Functional screening of genes regulated during growth of noninjured axons revealed CD2AP as a positive regulator of axon outgrowth. A novel association of CD2AP with TrkA and p85 suggests a distinct intracellular signaling pathway regulating growth of noninjured axons. This may also represent a novel mechanism of generating specificity in multifunctional NGF signaling. Divergent regulation of CD2AP in different axon growth conditions suggests that separate mechanisms exist for different modes of axon growth. CD2AP is the first signaling molecule associated with adult sensory axonal collateral sprouting, and this association may offer new insights for NGF/TrkA-related Alzheimer's disease mechanisms. PMID:27076424

Correlation of social cognition and neurocognition on psychotic outcome: a naturalistic follow-up study of subjects with attenuated psychosis syndrome

PubMed Central

Zhang, TianHong; Cui, HuiRu; Tang, YingYing; Xu, LiHua; Li, HuiJun; Wei, YanYan; Liu, XiaoHua; Chow, Annabelle; Li, ChunBo; Jiang, KaiDa; Xiao, ZePing; Wang, JiJun

2016-01-01

Neurocognitive decline has been observed in patients with psychosis as well as attenuated psychosis syndrome (APS). We tested the hypothesis that APS increases dependence on neurocognition during the interpretation of others’ mental states and that a combination index of Theory of Mind (ToM) and neurocognition improves the predictive accuracy of psychosis conversion. A sample of 83 APS individuals and 90 healthy controls (HC) were assessed by comprehensive cognitive tests. The cohort also completed a one-year follow-up. In the APS group, ToM was associated with an apparent increase in neurocognition, but this trend was not evident in the HC group. Using the new index of combined neurocognition and ToM scores, the sensitivity for predicting psychosis-proneness was 75% and the specificity was 69%. Our data suggest that the correlations between ToM function and neurocognition in APS subjects were stronger than those in healthy controls. A composite index of neurocognition and ToM could improve the predictive validity of a future conversion to psychosis. PMID:27721394

A percutaneous drainage protocol for severe and moderately severe acute pancreatitis.

PubMed

Sugimoto, Motokazu; Sonntag, David P; Flint, Greggory S; Boyce, Cody J; Kirkham, John C; Harris, Tyler J; Carr, Sean M; Nelson, Brent D; Barton, Joshua G; Traverso, L William

2015-11-01

According to the revised Atlanta classification, severe and moderately severe acute pancreatitis (AP) includes patients with pancreatic and peripancreatic collections with or without organ failure. These collections suggest the presence of pancreatic juice leakage. The aim of this study was to evaluate the efficacy of a percutaneous catheter drainage (PCD) protocol designed to control leakage and decrease disease severity. Among 663 patients with clinical AP, 122 were classified as moderately severe or severe AP (all had collections). The computed tomography severity index (CTSI) score was calculated. The indication for PCD was based on progressive clinical signs and symptoms. Drain patency, position, and need for additional drainage sites were assessed using CT scans and drain studies initially every 3 days using a proactive protocol. Drain fluid was examined for amylase concentration and microbiological culture. Clinicopathological variables for patients with and without PCD were compared. Since there was no mortality, we used prolonged drainage time to measure the success of PCD. Within the group treated with PCD, variables that resulted in prolonged drainage time were analyzed. PCD was used in 47/122 (39 %) patients of which 33/47 (70 %) had necrosis. PCD cases had a median CTSI of 8 and were classified as moderately severe AP (57 %) and severe AP (43 %). Inhospital mortality was zero. Surgical necrosectomy was not required for patients with necrosis. Independent risk factors for prolonged drainage time were persistent organ failure >48 h (P = 0.001), CTSI 8-10 (P = 0.038), prolonged duration of amylase-rich fluid in drains (P < 0.001), and polymicrobial culture fluid in drains (P = 0.015). A proactive PCD protocol persistently maintaining drain patency advanced to the site of leak controlled the prolonged amylase in drainage fluid resulting in a mortality rate of zero.

Initial segment Kv2.2 channels mediate a slow delayed rectifier and maintain high frequency action potential firing in medial nucleus of the trapezoid body neurons

PubMed Central

Johnston, Jamie; Griffin, Sarah J; Baker, Claire; Skrzypiec, Anna; Chernova, Tatanya; Forsythe, Ian D

2008-01-01

The medial nucleus of the trapezoid body (MNTB) is specialized for high frequency firing by expression of Kv3 channels, which minimize action potential (AP) duration, and Kv1 channels, which suppress multiple AP firing, during each calyceal giant EPSC. However, the outward K+ current in MNTB neurons is dominated by another unidentified delayed rectifier. It has slow kinetics and a peak conductance of ∼37 nS; it is half-activated at −9.2 ± 2.1 mV and half-inactivated at −35.9 ± 1.5 mV. It is blocked by several non-specific potassium channel antagonists including quinine (100 μm) and high concentrations of extracellular tetraethylammonium (TEA; IC50 = 11.8 mm), but no specific antagonists were found. These characteristics are similar to recombinant Kv2-mediated currents. Quantitative RT-PCR showed that Kv2.2 mRNA was much more prevalent than Kv2.1 in the MNTB. A Kv2.2 antibody showed specific staining and Western blots confirmed that it recognized a protein ∼110 kDa which was absent in brainstem tissue from a Kv2.2 knockout mouse. Confocal imaging showed that Kv2.2 was highly expressed in axon initial segments of MNTB neurons. In the absence of a specific antagonist, Hodgkin–Huxley modelling of voltage-gated conductances showed that Kv2.2 has a minor role during single APs (due to its slow activation) but assists recovery of voltage-gated sodium channels (Nav) from inactivation by hyperpolarizing interspike potentials during repetitive AP firing. Current-clamp recordings during high frequency firing and characterization of Nav inactivation confirmed this hypothesis. We conclude that Kv2.2-containing channels have a distinctive initial segment location and crucial function in maintaining AP amplitude by regulating the interspike potential during high frequency firing. PMID:18511484

A Dynamical Threshold for Cardiac Delayed Afterdepolarization-Mediated Triggered Activity.

PubMed

Liu, Michael B; Ko, Christopher Y; Song, Zhen; Garfinkel, Alan; Weiss, James N; Qu, Zhilin

2016-12-06

Ventricular myocytes are excitable cells whose voltage threshold for action potential (AP) excitation is ∼-60 mV at which I Na is activated to give rise to a fast upstroke. Therefore, for a short stimulus pulse to elicit an AP, a stronger stimulus is needed if the resting potential lies further away from the I Na threshold, such as in hypokalemia. However, for an AP elicited by a long duration stimulus or a diastolic spontaneous calcium release, we observed that the stimulus needed was lower in hypokalemia than in normokalemia in both computer simulations and experiments of rabbit ventricular myocytes. This observation provides insight into why hypokalemia promotes calcium-mediated triggered activity, despite the resting potential lying further away from the I Na threshold. To understand the underlying mechanisms, we performed bifurcation analyses and demonstrated that there is a dynamical threshold, resulting from a saddle-node bifurcation mainly determined by I K1 and I NCX . This threshold is close to the voltage at which I K1 is maximum, and lower than the I Na threshold. After exceeding this dynamical threshold, the membrane voltage will automatically depolarize above the I Na threshold due to the large negative slope of the I K1 -V curve. This dynamical threshold becomes much lower in hypokalemia, especially with respect to calcium, as predicted by our theory. Because of the saddle-node bifurcation, the system can automatically depolarize even in the absence of I Na to voltages higher than the I Ca,L threshold, allowing for triggered APs in single myocytes with complete I Na block. However, because I Na is important for AP propagation in tissue, blocking I Na can still suppress premature ventricular excitations in cardiac tissue caused by calcium-mediated triggered activity. This suppression is more effective in normokalemia than in hypokalemia due to the difference in dynamical thresholds. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The influence of material anisotropy on vibration at onset in a three-dimensional vocal fold model

PubMed Central

Zhang, Zhaoyan

2014-01-01

Although vocal folds are known to be anisotropic, the influence of material anisotropy on vocal fold vibration remains largely unknown. Using a linear stability analysis, phonation onset characteristics were investigated in a three-dimensional anisotropic vocal fold model. The results showed that isotropic models had a tendency to vibrate in a swing-like motion, with vibration primarily along the superior-inferior direction. Anterior-posterior (AP) out-of-phase motion was also observed and large vocal fold vibration was confined to the middle third region along the AP length. In contrast, increasing anisotropy or increasing AP-transverse stiffness ratio suppressed this swing-like motion and allowed the vocal fold to vibrate in a more wave-like motion with strong medial-lateral motion over the entire medial surface. Increasing anisotropy also suppressed the AP out-of-phase motion, allowing the vocal fold to vibrate in phase along the entire AP length. Results also showed that such improvement in vibration pattern was the most effective with large anisotropy in the cover layer alone. These numerical predictions were consistent with previous experimental observations using self-oscillating physical models. It was further hypothesized that these differences may facilitate complete glottal closure in finite-amplitude vibration of anisotropic models as observed in recent experiments. PMID:24606284

Acute pancreatitis decreases the sensitivity of pancreas-projecting dorsal motor nucleus of the vagus neurones to group II metabotropic glutamate receptor agonists in rats

PubMed Central

Babic, Tanja; Travagli, R Alberto

2014-01-01

Recent studies have shown that pancreatic exocrine secretions (PES) are modulated by dorsal motor nucleus of the vagus (DMV) neurones, whose activity is finely tuned by GABAergic and glutamatergic synaptic inputs. Group II metabotropic glutamate receptors (mGluR) decrease synaptic transmission to pancreas-projecting DMV neurones and increase PES. In the present study, we used a combination of in vivo and in vitro approaches aimed at characterising the effects of caerulein-induced acute pancreatitis (AP) on the vagal neurocircuitry modulating pancreatic functions. In control rats, microinjection of bicuculline into the DMV increased PES, whereas microinjections of kynurenic acid had no effect. Conversely, in AP rats, microinjection of bicuculline had no effect, whereas kynurenic acid decreased PES. DMV microinjections of the group II mGluR agonist APDC and whole cell recordings of excitatory currents in identified pancreas-projecting DMV neurones showed a reduced functional response in AP rats compared to controls. Moreover, these changes persisted up to 3 weeks following the induction of AP. These data demonstrate that AP increases the excitatory input to pancreas-projecting DMV neurones by decreasing the response of excitatory synaptic terminals to group II mGluR agonist. PMID:24445314

Melatonin attenuates inflammation of acute pulpitis subjected to dental pulp injury

PubMed Central

Li, Ji-Guo; Lin, Jia-Ji; Wang, Zhao-Ling; Cai, Wen-Ke; Wang, Pei-Na; Jia, Qian; Zhang, An-Sheng; Wu, Gao-Yi; Zhu, Guo-Xiong; Ni, Long-Xing

2015-01-01

Acute pulpitis (AP), one of the most common diseases in the endodontics, usually causes severe pain to the patients, which makes the search for therapeutic target of AP essential in clinic. Toll-like receptor 4 (TLR4) signaling is widely involved in the mechanism of pulp inflammation, while melatonin has been reported to have an inhibition for a various kinds of inflammation. We hereby studied whether melatonin can regulate the expression of TLR4/NF-ĸB signaling in the pulp tissue of AP and in human dental pulp cells (HDPCs). Two left dental pulps of the adult rat were drilled open to establish the AP model, and the serum levels of melatonin and pro-inflammatory cytokines, including interleukin 1β (IL-1β), interleukin 18 (IL-18) and tumor necrosis factor α (TNF-α), were assessed at 1, 3 and 5 d post injury. At the same time points, the expression of TLR4 signaling in the pulp was explored by quantitative real-time PCR and immunohistochemistry. The AP rats were administered an abdominal injection of melatonin to assess whether melatonin rescued AP and TLR4/NF-ĸB signaling. Dental pulp injury led to an approximately five-day period acute pulp inflammation and necrosis in the pulp and a significant up-regulation of IL-1β, IL-18 and TNF-α in the serum. ELISA results showed that the level of melatonin in the serum decreased due to AP, while an abdominal injection of melatonin suppressed the increase in serum cytokines and the percentage of necrosis at the 5 d of the injured pulp. Consistent with the inflammation in AP rats, TLR4, NF-ĸB, TNF-α and IL-1β in the pulp were increased post AP compared with the baseline expression. And melatonin showed an inhibition on TLR4/NF-ĸB signaling as well as IL-1β and TNF-α production in the pulp of AP rats. Furthermore, melatonin could also regulate the expression of TLR4/NF-ĸB signaling in LPS-stimulated HDPCs. These data suggested that dental pulp injury induced AP and reduced the serum level of melatonin and that supplementation with melatonin may have a protective effect on AP by modulating TLR4/NF-ĸB signaling in the pulp and in pulp cells. PMID:25755829

Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria

PubMed Central

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

Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria.

PubMed

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.

Localization and function of the Kv3.1b subunit in the rat medulla oblongata: focus on the nucleus tractus solitarii

PubMed Central

Dallas, Mark L; Atkinson, Lucy; Milligan, Carol J; Morris, Neil P; Lewis, David I; Deuchars, Susan A; Deuchars, Jim

2005-01-01

The voltage-gated potassium channel subunit Kv3.1 confers fast firing characteristics to neurones. Kv3.1b subunit immunoreactivity (Kv3.1b-IR) was widespread throughout the medulla oblongata, with labelled neurones in the gracile, cuneate and spinal trigeminal nuclei. In the nucleus of the solitary tract (NTS), Kv3.1b-IR neurones were predominantly located close to the tractus solitarius (TS) and could be GABAergic or glutamatergic. Ultrastructurally, Kv3.1b-IR was detected in NTS terminals, some of which were vagal afferents. Whole-cell current-clamp recordings from neurones near the TS revealed electrophysiological characteristics consistent with the presence of Kv3.1b subunits: short duration action potentials (4.2 ± 1.4 ms) and high firing frequencies (68.9 ± 5.3 Hz), both sensitive to application of TEA (0.5 mm) and 4-aminopyridine (4-AP; 30 μm). Intracellular dialysis of an anti-Kv3.1b antibody mimicked and occluded the effects of TEA and 4-AP in NTS and dorsal column nuclei neurones, but not in dorsal vagal nucleus or cerebellar Purkinje cells (which express other Kv3 subunits, but not Kv3.1b). Voltage-clamp recordings from outside-out patches from NTS neurones revealed an outward K+ current with the basic characteristics of that carried by Kv3 channels. In NTS neurones, electrical stimulation of the TS evoked EPSPs and IPSPs, and TEA and 4-AP increased the average amplitude and decreased the paired pulse ratio, consistent with a presynaptic site of action. Synaptic inputs evoked by stimulation of a region lacking Kv3.1b-IR neurones were not affected, correlating the presence of Kv3.1b in the TS with the pharmacological effects. PMID:15528247

Cannabinoid HU210 Protects Isolated Rat Stomach against Impairment Caused by Serum of Rats with Experimental Acute Pancreatitis

PubMed Central

Cao, Ming-hua; Li, Yong-yu; Xu, Jing; Feng, Ya-jing; Lin, Xu-hong; Li, Kun; Han, Tong; Chen, Chang-Jie

2012-01-01

Acute pancreatitis (AP), especially severe acute pancreatitis often causes extra-pancreatic complications, such as acute gastrointestinal mucosal lesion (AGML) which is accompanied by a considerably high mortality, yet the pathogenesis of AP-induced AGML is still not fully understood. In this report, we investigated the alterations of serum components and gastric endocrine and exocrine functions in rats with experimental acute pancreatitis, and studied the possible contributions of these alterations in the pathogenesis of AGML. In addition, we explored the intervention effects of cannabinoid receptor agonist HU210 and antagonist AM251 on isolated and serum-perfused rat stomach. Our results showed that the AGML occurred after 5 h of AP replication, and the body homeostasis was disturbed in AP rat, with increased levels of pancreatic enzymes, lipopolysaccharide (LPS), proinflammtory cytokines and chemokines in the blood, and an imbalance of the gastric secretion function. Perfusing the isolated rat stomach with the AP rat serum caused morphological changes in the stomach, accompanied with a significant increment of pepsin and [H+] release, and increased gastrin and decreased somatostatin secretion. HU210 reversed the AP-serum-induced rat pathological alterations, including the reversal of transformation of the gastric morphology to certain degree. The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis. PMID:23285225

Chlorogenic acid prevents acetaminophen-induced liver injury: the involvement of CYP450 metabolic enzymes and some antioxidant signals*

PubMed Central

Pang, Chun; Sheng, Yu-chen; Jiang, Ping; Wei, Hai; Ji, Li-li

2015-01-01

Chlorogenic acid (CGA), a polyphenolic compound, is abundant in fruits, dietary vegetables, and some medicinal herbs. This study investigated the prevention of CGA against acetaminophen (AP)-induced hepatotoxicity and its engaged mechanisms. CGA reversed the decreased cell viability induced by AP in L-02 cells in vitro. In addition, CGA reduced the AP-induced increased serum levels of alanine/aspartate aminotransferase (ALT/AST) in vivo. The effect of CGA on cytochrome P450 (CYP) enzymatic (CYP2E1, CYP1A2, and CYP3A4) activities showed that CGA caused very little inhibition on CYP2E1 and CYP1A2 enzymatic activities, but not CYP3A4. The measurement of liver malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH) levels showed that CGA prevented AP-induced liver oxidative stress injury. Further, CGA increased the AP-induced decreased mRNA expression of peroxiredoxin (Prx) 1, 2, 3, 5, 6, epoxide hydrolase (Ephx) 2, and polymerase (RNA) II (DNA directed) polypeptide K (Polr2k), and nuclear factor erythroid-2-related factor 2 (Nrf2). In summary, CGA ameliorates the AP-induced liver injury probably by slightly inhibiting CYP2E1 and CYP1A2 enzymatic properties. In addition, cellular important antioxidant signals such as Prx1, 2, 3, 5, 6, Ephx2, Polr2k, and Nrf2 also contributed to the protection of CGA against AP-induced oxidative stress injury. PMID:26160718

Evidence for a G protein-coupled diadenosine-5',5'''-P1,P4-tetraphosphate (Ap4A) receptor binding site in lung membranes from rat.

PubMed

Laubinger, W; Reiser, G

1999-01-29

Nucleotide receptors are of considerable importance in the treatment of lung diseases, such as cystic fibrosis. Because diadenosine polyphosphates may also be of significance as signalling molecules in lung, as they are in a variety of tissues, in the present work we investigated the binding sites for [3H]diadenosine-5',5'''-P1,P4-tetraphosphate (Ap4A) in plasma membranes from rat lung and studied their possible coupling to G proteins. We present evidence for a single high-affinity binding site for [3H]Ap4A with similar affinity for other diadenosine polyphosphates ApnA (n = 2 to 6). Displacement studies with different nucleotides revealed that the [3H]Ap4A binding site was different from P2X and P2Y2 receptor binding sites. Pretreatment of lung membranes with GTPgammaS or GTP in the presence of Mg2+ increased the Ki for Ap4A from 91 nM to 5.1 microM, which is indicative of G protein coupling. The putative coupling to G proteins was further confirmed by the enhancement of [35S]GTPgammaS binding (to Galpha proteins) to lung membranes by Ap4A (63% increase over basal) in a concentration-dependent manner. Therefore, our data for the first time provide evidence of a G protein-coupled Ap4A binding site in lung membranes.

Is Increased Access Enough? Advanced Placement Courses, Quality, and Success in Low-Income Urban Schools

ERIC Educational Resources Information Center

Hallett, Ronald E.; Venegas, Kristan M.

2011-01-01

This article combines descriptive statistics and interviews with college-bound high school students to explore the connection between increased access and academic quality of Advanced Placement (AP) courses in low-income urban high schools. Results suggest that although moderately more opportunities to take AP courses exist than in previous years,…

Characteristics of the isomeric flavonoids apigenin and genistein binding to hemoglobin by spectroscopic methods

NASA Astrophysics Data System (ADS)

Yuan, Jiang-Lan; Liu, Hui; Kang, Xu; Lv, Zhong; Zou, Guo-Lin

2008-11-01

Apigenin (Ap) and genistein (Ge), a couple of isomeric flavonoids with extensive bioactivities, are the most common dietary ingredients. They have been widely investigated due to their potential therapeutic actions for some diseases. In our work, binding characteristics of Ap and Ge to hemoglobin (Hb) were analyzed with fluorescence spectroscopy, circular dichroism (CD) and UV-vis absorption spectroscopy. The results indicated that Ap and Ge caused strong fluorescence quenching of Hb by static quenching mechanism, but their quenching efficiency and mechanisms were different. The binding site n suggested that there was a single binding site in Hb for Ap and Ge. The results of synchronous fluorescence showed that the microenvironment around Tyr residues of Hb had a slight trend of polarity decreasing, but the polarity around Trp residues increased by adding Ap. Results of CD indicated that the Ap and Ge did not changed the secondary structure of Hb. According to the theory of Förster resonance energy transfer, the binding distance r between Trp 37 and Ap/Ge was predicted to be 3.4 nm and 3.32 nm, respectively. The affinity of Ge toward Hb was higher than that of Ap.

Ca(2+)-stores mobilization by diadenosine tetraphosphate, Ap4A, through a putative P2Y purinoceptor in adrenal chromaffin cells.

PubMed Central

Castro, E.; Pintor, J.; Miras-Portugal, M. T.

1992-01-01

1. Diadenosine tetraphosphate (Ap4A) evoked a concentration-dependent increase in cytosolic [Ca2+] in resting chromaffin cells. The EC50 value for this action was 28.2 +/- 6.6 microM. This effect was also produced by diadenosine pentaphosphate (Ap5A) with an EC50 of 50 +/- 7 microM. 2. In contrast with this effect, pretreatment with Ap4A or Ap5A induced a 30% reduction in Ca2+ entry following 10 microM dimethylphenylpiperazinium. 3. The elevation in cytosolic [Ca2+] induced by Ap4A was persistent in approximately 100 nM external [Ca2+] and was sensitive to depletion of internal Ca2+ stores by a bradykinin prepulse or whole cell depletion in Ca2+. 4. The effect of Ap4A was mimicked and desensitized by the agonist adenosine 5'-O-(2-thiodiphosphate), and blocked by the P2Y-receptor antagonist, cibachrome blue. The P2X-receptor agonist alpha,beta-methylene adenosine 5'-triphosphate was inactive both by itself or in combination with Ap4A. This is compatible with a P2Y-purinoceptor-mediated action. PMID:1393282

Ca(2+)-stores mobilization by diadenosine tetraphosphate, Ap4A, through a putative P2Y purinoceptor in adrenal chromaffin cells.

PubMed

Castro, E; Pintor, J; Miras-Portugal, M T

1992-08-01

1. Diadenosine tetraphosphate (Ap4A) evoked a concentration-dependent increase in cytosolic [Ca2+] in resting chromaffin cells. The EC50 value for this action was 28.2 +/- 6.6 microM. This effect was also produced by diadenosine pentaphosphate (Ap5A) with an EC50 of 50 +/- 7 microM. 2. In contrast with this effect, pretreatment with Ap4A or Ap5A induced a 30% reduction in Ca2+ entry following 10 microM dimethylphenylpiperazinium. 3. The elevation in cytosolic [Ca2+] induced by Ap4A was persistent in approximately 100 nM external [Ca2+] and was sensitive to depletion of internal Ca2+ stores by a bradykinin prepulse or whole cell depletion in Ca2+. 4. The effect of Ap4A was mimicked and desensitized by the agonist adenosine 5'-O-(2-thiodiphosphate), and blocked by the P2Y-receptor antagonist, cibachrome blue. The P2X-receptor agonist alpha,beta-methylene adenosine 5'-triphosphate was inactive both by itself or in combination with Ap4A. This is compatible with a P2Y-purinoceptor-mediated action.

Ligand-induced changes in 2-aminopurine fluorescence as a probe for small molecule binding to HIV-1 TAR RNA

PubMed Central

BRADRICK, THOMAS D.; MARINO, JOHN P.

2004-01-01

Replication of human immunodeficiency virus type 1 (HIV-1) is regulated in part through an interaction between the virally encoded trans-activator protein Tat and the trans-activator responsive region (TAR) of the viral RNA genome. Because TAR is highly conserved and its interaction with Tat is required for efficient viral replication, it has received much attention as an antiviral drug target. Here, we report a 2-aminopurine (2-AP) fluorescence-based assay for evaluating potential TAR inhibitors. Through selective incorporation of 2-AP within the bulge (C23 or U24) of a truncated form of the TAR sequence (Δ TAR-ap23 and Δ TAR-ap24), binding of argininamide, a 24-residue arginine-rich peptide derived from Tat, and Neomycin has been characterized using steady-state fluorescence. Binding of argininamide to the 2-AP ΔTAR constructs results in a four- to 11-fold increase in fluorescence intensity, thus providing a sensitive reporter of that interaction (KD ~ 1 mM). Similarly, binding of the Tat peptide results in an initial 14-fold increase in fluorescence (KD ~ 25 nM), but is then followed by a slight decrease that is attributed to an additional, lower-affinity association(s). Using the ΔTAR-ap23 and TAR-ap24 constructs, two classes of Neomycin binding sites are detected; the first molecule of antibiotic binds as a noncompetitive inhibitor of Tat/argininamide (KD ~ 200 nM), whereas the second, more weakly bound molecule(s) becomes associated in a presumably nonspecific manner (KD ~ 4 μM). Taken together, the results demonstrate that the 2-AP fluorescence-detected binding assays provide accurate and general methods for quantitatively assessing TAR interactions. PMID:15273324

Heterozygous disruption of activin receptor-like kinase 1 is associated with increased arterial pressure in mice

PubMed Central

González-Núñez, María; Riolobos, Adela S.; Castellano, Orlando; Fuentes-Calvo, Isabel; de los Ángeles Sevilla, María; Oujo, Bárbara; Pericacho, Miguel; Cruz-Gonzalez, Ignacio; Pérez-Barriocanal, Fernando; ten Dijke, Peter; López-Novoa, Jose M.

2015-01-01

ABSTRACT The activin receptor-like kinase 1 (ALK-1) is a type I cell-surface receptor for the transforming growth factor-β (TGF-β) family of proteins. Hypertension is related to TGF-β1, because increased TGF-β1 expression is correlated with an elevation in arterial pressure (AP) and TGF-β expression is upregulated by the renin-angiotensin-aldosterone system. The purpose of this study was to assess the role of ALK-1 in regulation of AP using Alk1 haploinsufficient mice (Alk1+/−). We observed that systolic and diastolic AP were significantly higher in Alk1+/− than in Alk1+/+ mice, and all functional and structural cardiac parameters (echocardiography and electrocardiography) were similar in both groups. Alk1+/− mice showed alterations in the circadian rhythm of AP, with higher AP than Alk1+/+ mice during most of the light period. Higher AP in Alk1+/− mice is not a result of a reduction in the NO-dependent vasodilator response or of overactivation of the peripheral renin-angiotensin system. However, intracerebroventricular administration of losartan had a hypotensive effect in Alk1+/− and not in Alk1+/+ mice. Alk1+/− mice showed a greater hypotensive response to the β-adrenergic antagonist atenolol and higher concentrations of epinephrine and norepinephrine in plasma than Alk1+/+ mice. The number of brain cholinergic neurons in the anterior basal forebrain was reduced in Alk1+/− mice. Thus, we concluded that the ALK-1 receptor is involved in the control of AP, and the high AP of Alk1+/− mice is explained mainly by the sympathetic overactivation shown by these animals, which is probably related to the decreased number of cholinergic neurons. PMID:26398936

Exogenous alkaline phosphatase treatment complements endogenous enzyme protection in colonic inflammation and reduces bacterial translocation in rats.

PubMed

Martínez-Moya, P; Ortega-González, M; González, R; Anzola, A; Ocón, B; Hernández-Chirlaque, C; López-Posadas, R; Suárez, M D; Zarzuelo, A; Martínez-Augustin, O; Sánchez de Medina, F

2012-08-01

Alkaline phosphatase (AP) inactivates bacterial lipopolysaccharide and may therefore be protective. The small intestine and colon express intestinal (IAP) and tissue nonspecific enzyme (TNAP), respectively. The aim of this study was to assess the therapeutic potential of exogenous AP and its complementarity with endogenous enzyme protection in the intestine, as evidenced recently. IAP was given to rats by the oral or intrarectal route (700U/kgday). Oral budesonide (1mg/kgday) was used as a reference treatment. Treatment with intrarectal AP resulted in a 54.5% and 38.0% lower colonic weight and damage score, respectively, and an almost complete normalization of the expression of S100A8, LCN2 and IL-1β (p<0.05). Oral AP was less efficacious, while budesonide had a more pronounced effect on most parameters. Both oral and intrarectal AP counteracted bacterial translocation effectively (78 and 100%, respectively, p<0.05 for the latter), while budesonide failed to exert a positive effect. AP activity was increased in the feces of TNBS colitic animals, associated with augmented sensitivity to the inhibitor levamisole, suggesting enhanced luminal release of this enzyme. This was also observed in the mouse lymphocyte transfer model of chronic colitis. In a separate time course study, TNAP was shown to increase 2-3 days after colitis induction, while dextran sulfate sodium was a much weaker inducer of this isoform. We conclude that exogenous AP exerts beneficial effects on experimental colitis, which includes protection against bacterial translocation. AP of the tissue-nonspecific isoform is shed in higher amounts to the intestinal lumen in experimental colitis, possibly aiding in intestinal protection. Copyright © 2012 Elsevier Ltd. All rights reserved.

Low concentrations of copper in drinking water increase AP-1 binding in the brain.

PubMed

Lung, Shyang; Li, Huihui; Bondy, Stephen C; Campbell, Arezoo

2015-12-01

Copper (Cu) in trace amounts is essential for biological organisms. However, dysregulation of the redox-active metal has been implicated in different neurological disorders such as Wilson's, Menkes', Alzheimer's, and Parkinson's diseases. Since many households use Cu tubing in the plumbing system, and corrosion causes the metal to leach into the drinking water, there may be adverse effects on the central nervous system connected with low-level chronic exposure. The present study demonstrates that treatment with a biologically relevant concentration of Cu for 3 months significantly increases activation of the redox-modulated transcription factor AP-1 in mouse brains. This was independent of an upstream kinase indicated in AP-1 activation. Another redox-active transcription factor, NF-κB, was not significantly modified by the Cu exposure. These results indicate that the effect of Cu on AP-1 is unique and may involve direct modulation of DNA binding. © The Author(s) 2012.

Noise and complexity in human postural control: interpreting the different estimations of entropy.

PubMed

Rhea, Christopher K; Silver, Tobin A; Hong, S Lee; Ryu, Joong Hyun; Studenka, Breanna E; Hughes, Charmayne M L; Haddad, Jeffrey M

2011-03-17

Over the last two decades, various measures of entropy have been used to examine the complexity of human postural control. In general, entropy measures provide information regarding the health, stability and adaptability of the postural system that is not captured when using more traditional analytical techniques. The purpose of this study was to examine how noise, sampling frequency and time series length influence various measures of entropy when applied to human center of pressure (CoP) data, as well as in synthetic signals with known properties. Such a comparison is necessary to interpret data between and within studies that use different entropy measures, equipment, sampling frequencies or data collection durations. The complexity of synthetic signals with known properties and standing CoP data was calculated using Approximate Entropy (ApEn), Sample Entropy (SampEn) and Recurrence Quantification Analysis Entropy (RQAEn). All signals were examined at varying sampling frequencies and with varying amounts of added noise. Additionally, an increment time series of the original CoP data was examined to remove long-range correlations. Of the three measures examined, ApEn was the least robust to sampling frequency and noise manipulations. Additionally, increased noise led to an increase in SampEn, but a decrease in RQAEn. Thus, noise can yield inconsistent results between the various entropy measures. Finally, the differences between the entropy measures were minimized in the increment CoP data, suggesting that long-range correlations should be removed from CoP data prior to calculating entropy. The various algorithms typically used to quantify the complexity (entropy) of CoP may yield very different results, particularly when sampling frequency and noise are different. The results of this study are discussed within the context of the neural noise and loss of complexity hypotheses.

The proliferative and chronotropic effects of Brillantaisia nitens Lindau (Acanthaceae) extracts on pluripotent stem cells and their cardiomyocytes derivatives.

PubMed

Nembo, Erastus Nembu; Dimo, Theophile; Bopda, Orelien Sylvain Mtopi; Hescheler, Jürgen; Nguemo, Filomain

2014-10-28

Brillantaisia nitens Lindau (Acanthaceae) leaves are commonly used in traditional medicine in Africa for the treatment of many disorders including heart diseases and malaria. In this study, we therefore evaluated the effect of the methylene chloride/methanol leaf extract of Brillantaisia nitens on the proliferation of mouse pluripotent stem cells and their cardiomyocyte derivatives. In this study, we combined two emerging technologies, pluripotent stem cell-derived cardiomyocytes and modern electrophysiology systems (impedance-based real-time) to assess the cytotoxicity of Brillantaisia nitens extract (BNE). Undifferentiated pluripotent cells and cardiomyocytes were exposed to different concentrations of BNE. Cell viability and contraction were monitored by impedance using the xCELLigence system for short- and long-term treatment whereas the excitability of single cardiomyocytes was captured by patch clamp technique after BNE acute exposure. Brillantaisia nitens extract inhibited the proliferation and increased cytotoxicity of embryonic stem cells in a concentration-dependent manner. With the increase in concentration of BNE, beating rate and the contractile amplitude of cardiomyocytes changed significantly. Spontaneous rhythmic activity of cardiomyocytes was completely suppressed after 48 and 24h exposures to relatively low (4.16 mg/ml) and high (8.32 mg/ml) concentrations of BNE, respectively. Moreover, acute application of 4.16 mg/ml of BNE led to a significant alteration of action potential (AP) parameters such as beating frequency, amplitude and AP duration at 90% of repolarization. Brillantaisia nitens extract inhibits the proliferative capacity of pluripotent stem cells and reduces electrical activity of cardiomyocytes, confirming its depressant action on the heart. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Reduction of I(Ca,L) and I(to1) density in hypertrophied right ventricular cells by simulated high altitude in adult rats.

PubMed

Chouabe, C; Espinosa, L; Megas, P; Chakir, A; Rougier, O; Freminet, A; Bonvallet, R

1997-01-01

The present paper describes the effect of a simulated hypobaric condition (at the altitude of 4500 m) on morphological characteristics and on some ionic currents in ventricular cells of adult rats. According to current data, chronic high-altitude exposure led to mild right ventricular hypertrophy. Increase in right ventricular weight appeared to be due wholly or partly to an enlargement of myocytes. The whole-cell patch-clamp technique was used and this confirmed, by cell capacitance measurement, that chronic high-altitude exposure induced an increase in the size of the right ventricular cells. Hypertrophied cells showed prolongation of action potential (AP). Four ionic currents, playing a role along with many others in the precise balance of inward and outward currents that control the duration of cardiac AP, were investigated. We report a significant decrease in the transient outward (I(to1)) and in the L-type calcium current (I(Ca,L)) densities while there was no significant difference in the delayed rectifier current (I(K)) or in the inward rectifier current (I(K1)) densities in hypertrophied right ventricular cells compared to control cells. At a given potential the decrease in I(to 1) density was relatively more important than the decrease in I(Ca,L) density. In both cell types, all the currents displayed the same voltage dependence. The inactivation kinetics of I(to 1) and I(Ca,L) or the steady-state activation and inactivation relationships were not significantly modified by chronic high-altitude exposure. We conclude that chronic high-altitude exposure induced true right ventricular myocyte hypertrophy and that the decrease in I(to 1) density might account for the lengthened action potential, or have a partial effect.

Na+ current in presynaptic terminals of the crayfish opener cannot initiate action potentials.

PubMed

Lin, Jen-Wei

2016-01-01

Action potential (AP) propagation in presynaptic axons of the crayfish opener neuromuscular junction (NMJ) was investigated by simultaneously recording from a terminal varicosity and a proximal branch. Although orthodromically conducting APs could be recorded in terminals with amplitudes up to 70 mV, depolarizing steps in terminals to -20 mV or higher failed to fire APs. Patch-clamp recordings did detect Na(+) current (INa) in most terminals. The INa exhibited a high threshold and fast activation rate. Local perfusion of Na(+)-free saline showed that terminal INa contributed to AP waveform by slightly accelerating the rising phase and increasing the peak amplitude. These findings suggest that terminal INa functions to "touch up" but not to generate APs. Copyright © 2016 the American Physiological Society.

Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration

PubMed Central

Dubos, Aline; Castells-Nobau, Anna; Meziane, Hamid; Oortveld, Merel A.W.; Houbaert, Xander; Iacono, Giovanni; Martin, Christelle; Mittelhaeuser, Christophe; Lalanne, Valérie; Kramer, Jamie M.; Bhukel, Anuradha; Quentin, Christine; Slabbert, Jan; Verstreken, Patrik; Sigrist, Stefan J.; Messaddeq, Nadia; Birling, Marie-Christine; Selloum, Mohammed; Stunnenberg, Henk G.; Humeau, Yann; Schenck, Annette; Herault, Yann

2015-01-01

ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2Camk2aCre/0 mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2Camk2aCre/0 mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2Camk2aCre/0 mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2Camk2aCre/0 mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system. PMID:26376863

Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.

PubMed

Dubos, Aline; Castells-Nobau, Anna; Meziane, Hamid; Oortveld, Merel A W; Houbaert, Xander; Iacono, Giovanni; Martin, Christelle; Mittelhaeuser, Christophe; Lalanne, Valérie; Kramer, Jamie M; Bhukel, Anuradha; Quentin, Christine; Slabbert, Jan; Verstreken, Patrik; Sigrist, Stefan J; Messaddeq, Nadia; Birling, Marie-Christine; Selloum, Mohammed; Stunnenberg, Henk G; Humeau, Yann; Schenck, Annette; Herault, Yann

2015-12-01

ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2(Camk2aCre/0) mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2(Camk2aCre/0) mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2(Camk2aCre/0) mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2(Camk2aCre/0) mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system. © The Author 2015. Published by Oxford University Press.

Comparison of Clinical Characteristics and Outcomes of Patients With Versus Without Diabetes Mellitus and With Versus Without Angina Pectoris (from the Duke Databank for Cardiovascular Disease).

PubMed

Banks, Adam; Broderick, Samuel; Chiswell, Karen; Shaw, Linda; Devore, Adam; Fiuzat, Mona; O'Connor, Christopher; Felker, Gary Michael; Velazquez, Eric; Mentz, Robert

2017-06-01

Angina pectoris (AP) has different prognostic implications in various populations. Patients with diabetes mellitus (DM) may experience neuropathy such that AP may not be perceived in the setting of coronary artery disease (CAD). The prognostic utility of AP in DM patients with CAD is not well known. We analyzed patients with CAD who underwent coronary angiography at Duke University from 2002 to 2011 and compared patients with and without AP within the previous 6 weeks stratified by DM status. We used multivariable Cox regression to assess the association between AP and the outcomes of cardiovascular (CV) hospitalization/revascularization, all-cause mortality/myocardial infarction/revascularization, and all-cause mortality. Of 17,211 patients with CAD, 5,284 (31%) had DM and AP was present in 69% of DM and 67% of non-DM. After risk adjustment, the risk of CV hospitalization/revascularization and all-cause mortality/myocardial infarction/revascularization in patients with and without AP was similar regardless of DM status (all p ≥0.05). In patients with or without DM, AP was associated with lower all-cause mortality compared with no AP (adjusted hazard ratio 0.89, 95% confidence interval 0.82 to 0.97, p = 0.005 for DM patients). The relation between AP status and clinical outcomes was not dependent on DM status (all interaction p >0.10). In conclusion, in patients with CAD, AP was associated with similar risk for CV hospitalization and revascularization and lower all-cause mortality compared with patients without AP regardless of DM status. Future studies are needed to assess whether these findings are related to increased severity of disease in those without AP or whether AP leads to differential management that improves survival. Copyright © 2017 Elsevier Inc. All rights reserved.

Kinetic and thermodynamic studies of bovine serum albumin interaction with ascorbyl palmitate and ascorbyl stearate food additives using surface plasmon resonance.

PubMed

Fathi, Farzaneh; Mohammadzadeh-Aghdash, Hossein; Sohrabi, Yousef; Dehghan, Parvin; Ezzati Nazhad Dolatabadi, Jafar

2018-04-25

Ascorbyl palmitate (AP) and ascorbyl stearate (AS) are examples of food additives, which have extensive use in food industry. In this study, we evaluated the interaction of bovine serum albumin (BSA) with AP and AS using surface plasmon resonance (SPR). In order to immobilize BSA, carboxymethyl dextran hydrogel (CMD) Au chip was used. After activation of carboxylic groups, BSA was immobilized onto the CMD chip through covalent amide binding formation. AP and AS binding to immobilized BSA at different concentrations was assessed. The dose-response sensorgrams of BSA upon increasing concentration of AP and AS have been shown. The low value of equilibrium dissociation constant or affinity unit (K D ) showed high affinity of both AP and AS to BSA. The K D value for binding of AP and AS to BSA were 4.09 × 10 -5 and 1.89 × 10 -5 , at 25 °C. Overall, the attained results showed that AP and AS molecules can bind to BSA. Copyright © 2017 Elsevier Ltd. All rights reserved.

A glossary of terms for understanding political aspects in the implementation of Health in All Policies (HiAP).

PubMed

Oneka, Goldameir; Vahid Shahidi, Faraz; Muntaner, Carles; Bayoumi, Ahmed M; Mahabir, Deb Finn; Freiler, Alix; O'Campo, Patricia; Shankardass, Ketan

2017-08-01

Health in All Policies (HiAP) is a strategy that seeks to integrate health considerations into the development, implementation and evaluation of policies across various non-health sectors of the government. Over the past 15 years, there has been an increase in the uptake of HiAP by local, regional and national governments. Despite the growing popularity of this approach, most existing literature on HiAP implementation remains descriptive rather than explanatory in its orientation. Moreover, prior research has focused on the more technical aspects of the implementation process. Thus, studies that aim to 'build capacity to promote, implement and evaluate HiAP' abound. Conversely, there is little emphasis on the political aspects of HiAP implementation. Neglecting the role of politics in shaping the use of HiAP is problematic, since health and the strategies by which it is promoted are partially political.This glossary addresses the politics gap in the existing literature by drawing on theoretical concepts from political, policy, and public health sciences to articulate a framework for studying how political mechanisms influence HiAP implementation. To this end, the glossary forms part of an on-going multiple explanatory case study of HiAP implementation, HARMONICS (HiAP Analysis using Realist Methods on International Case Studies, harmonics-hiap.ca), and is meant to expand on a previously published glossary addressing the topic of HiAP implementation more broadly. Collectively, these glossaries offer a conceptual toolkit for understanding how politics explains implementation outcomes of HiAP. © 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.

Prospective, Multicentre, Nationwide Clinical Data from 600 Cases of Acute Pancreatitis

PubMed Central

Párniczky, Andrea; Kui, Balázs; Szentesi, Andrea; Balázs, Anita; Szűcs, Ákos; Mosztbacher, Dóra; Czimmer, József; Sarlós, Patrícia; Bajor, Judit; Gódi, Szilárd; Vincze, Áron; Illés, Anita; Szabó, Imre; Pár, Gabriella; Takács, Tamás; Czakó, László; Szepes, Zoltán; Rakonczay, Zoltán; Izbéki, Ferenc; Gervain, Judit; Halász, Adrienn; Novák, János; Crai, Stefan; Hritz, István; Góg, Csaba; Sümegi, János; Golovics, Petra; Varga, Márta; Bod, Barnabás; Hamvas, József; Varga-Müller, Mónika; Papp, Zsuzsanna; Sahin-Tóth, Miklós; Hegyi, Péter

2016-01-01

Objective The aim of this study was to analyse the clinical characteristics of acute pancreatitis (AP) in a prospectively collected, large, multicentre cohort and to validate the major recommendations in the IAP/APA evidence-based guidelines for the management of AP. Design Eighty-six different clinical parameters were collected using an electronic clinical research form designed by the Hungarian Pancreatic Study Group. Patients 600 adult patients diagnosed with AP were prospectively enrolled from 17 Hungarian centres over a two-year period from 1 January 2013. Main Results With respect to aetiology, biliary and alcoholic pancreatitis represented the two most common forms of AP. The prevalence of biliary AP was higher in women, whereas alcoholic AP was more common in men. Hyperlipidaemia was a risk factor for severity, lack of serum enzyme elevation posed a risk for severe AP, and lack of abdominal pain at admission demonstrated a risk for mortality. Abdominal tenderness developed in all the patients with severe AP, while lack of abdominal tenderness was a favourable sign for mortality. Importantly, lung injury at admission was associated with mortality. With regard to laboratory parameters, white blood cell count and CRP were the two most sensitive indicators for severe AP. The most common local complication was peripancreatic fluid, whereas the most common distant organ failure in severe AP was lung injury. Deviation from the recommendations in the IAP/APA evidence-based guidelines on fluid replacement, enteral nutrition and timing of interventions increased severity and mortality. Conclusions Analysis of a large, nationwide, prospective cohort of AP cases allowed for the identification of important determinants of severity and mortality. Evidence-based guidelines should be observed rigorously to improve outcomes in AP. PMID:27798670

Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome

PubMed Central

De Pace, Raffaella; Damme, Markus; Mattera, Rafael; Jarnik, Michal; Hoffmann, Victoria; Morris, H. Douglas; Han, Tae-Un; Mancini, Grazia M. S.; Buonanno, Andrés

2018-01-01

The hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity. Mutations in subunits of the heterotetrameric (ε-β4-μ4-σ4) adaptor protein 4 (AP-4) complex cause an autosomal recessive form of complicated HSP referred to as “AP-4 deficiency syndrome”. In addition to lower limb spasticity, this syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity. The pathogenetic mechanism, however, remains poorly understood. Here we report the characterization of a knockout (KO) mouse for the AP4E1 gene encoding the ε subunit of AP-4. We find that AP-4 ε KO mice exhibit a range of neurological phenotypes, including hindlimb clasping, decreased motor coordination and weak grip strength. In addition, AP-4 ε KO mice display a thin corpus callosum and axonal swellings in various areas of the brain and spinal cord. Immunohistochemical analyses show that the transmembrane autophagy-related protein 9A (ATG9A) is more concentrated in the trans-Golgi network (TGN) and depleted from the peripheral cytoplasm both in skin fibroblasts from patients with mutations in the μ4 subunit of AP-4 and in various neuronal types in AP-4 ε KO mice. ATG9A mislocalization is associated with increased tendency to accumulate mutant huntingtin (HTT) aggregates in the axons of AP-4 ε KO neurons. These findings indicate that the AP-4 ε KO mouse is a suitable animal model for AP-4 deficiency syndrome, and that defective mobilization of ATG9A from the TGN and impaired autophagic degradation of protein aggregates might contribute to neuroaxonal dystrophy in this disorder. PMID:29698489

Beta-hydroxybutyrate Concentrations in Dogs with Acute Pancreatitis and Without Diabetes Mellitus.

PubMed

Hurrell, F E; Drobatz, K J; Hess, R S

2016-05-01

β-hydroxybutyrate (BOHB) concentrations have not been quantified in dogs with acute pancreatitis (AP). The aim of this study was to investigate BOHB concentrations in dogs with AP. A total of 154 client-owned dogs without DM. Prospective clinical study. Dogs were enrolled into 1 of 3 groups: AP, sick without an AP diagnosis, or fasted. Dogs were diagnosed with AP (44) if they had vomiting or anorexia, and either ultrasonographic findings consistent with AP or increased pancreatic lipase. Sick dogs without AP (68) had vomiting or anorexia but a diagnosis of AP was either not suspected or was excluded based on ultrasonographic findings or a normal pancreatic lipase. Dogs without anorexia or vomiting that were fasted for over 10 hours for a procedure were also enrolled (42). BOHB was measured on whole blood with a portable ketone meter. The Kruskal-Wallis test was performed to compare BOHB in the 3 groups. Pair-wise comparisons were performed using the Mann-Whitney test and Bonferroni corrected P-values are reported. Median BOHB concentration was significantly higher in dogs with AP (0.3 mmol/L, range 0-2.9 mmol/L) compared to sick dogs without AP (0.20 mmol/L, range 0-0.9 mmol/L, P = .007) and fasted dogs (0.1 mmol/L, range 0-0.4 mmol/L, P = .0001). Median BOHB concentration was significantly higher in sick dogs without AP compared to fasted dogs (P = .0002). In dogs without DM, BOHB is significantly higher in dogs with AP compared to other dogs. The diagnostic utility of this finding remains to be investigated. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

WCPSS Advanced Placement (AP) Results, 2011-12 and 2012-13. Measuring Up. D&A Report No. 13.17

ERIC Educational Resources Information Center

Muli, Juliana; McMillen, Brad

2014-01-01

Students in Wake County Public Schools (WCPSS) continue to score well on AP exams with an increased percentage of students enrolling in the courses. As in past years, in 2013 the district had higher average AP exam scores compared to the state and the nation. WCPSS had 76.6% of scores 3 or higher in 2013 (qualified and above). Again in both 2012…

Endotoxin- and ATP-neutralizing activity of alkaline phosphatase as a strategy to limit neuroinflammation

PubMed Central

2012-01-01

Background Alkaline phosphatase (AP) is a ubiquitously expressed enzyme which can neutralize endotoxin as well as adenosine triphosphate (ATP), an endogenous danger signal released during brain injury. In this study we assessed a potential therapeutic role for AP in inhibiting neuroinflammation using three complementary approaches. Methods Mice were immunized to induce experimental autoimmune encephalomyelitis (EAE) and treated with AP for seven days during different phases of disease. In addition, serological assays to determine AP activity, endotoxin levels and endotoxin-reactive antibodies were performed in a cohort of multiple sclerosis (MS) patients and controls. Finally, the expression of AP and related enzymes CD39 and CD73 was investigated in brain tissue from MS patients and control subjects. Results AP administration during the priming phase, but not during later stages, of EAE significantly reduced neurological signs. This was accompanied by reduced proliferation of splenocytes to the immunogen, myelin oligodendrocyte glycoprotein peptide. In MS patients, AP activity and isoenzyme distribution were similar to controls. Although endotoxin-reactive IgM was reduced in primary-progressive MS patients, plasma endotoxin levels were not different between groups. Finally, unlike AP and CD73, CD39 was highly upregulated on microglia in white matter lesions of patients with MS. Conclusions Our findings demonstrate that: 1) pre-symptomatic AP treatment reduces neurological signs of EAE; 2) MS patients do not have altered circulating levels of AP or endotoxin; and 3) the expression of the AP-like enzyme CD39 is increased on microglia in white matter lesions of MS patients. PMID:23231745

Characterization of a diadenosine tetraphosphate-receptor distinct from the ATP-purinoceptor in human tracheal gland cells.

PubMed

Saleh, A; Picher, M; Kammouni, W; Figarella, C; Merten, M D

1999-11-12

Human submucosal tracheal glands are now believed to play a major role in the physiopathology of cystic fibrosis, a genetic disease in which ATP is used as a therapeutic agent. However, actions of ATP on tracheal gland cells are not well known. ATP binds to P2 receptors and induced secretory leucocyte protease inhibitor (SLPI) secretion through formation of cyclic adenosine monophosphate and mobilization of intracellular [Ca(2+)]. Since diadenosine polyphosphates (ApnA) are also endogenous effectors of P2 receptors, we investigated their effects in a cell line (MM39) of human tracheal gland cells. Diadenosine tetraphosphates (Ap4A) induced significant stimulation (+50+/-12%) of SLPI secretion and to a similar extent to that of ATP (+65+/-10%). No significant effects were observed with diadenosine triphosphate (Ap3A), diadenosine pentaphosphate (Ap5A), ADP and 2-methylthio-adenosine triphosphate (2-MeS-ATP). Since Ap4A was weakly hydrolyzed (<2% of total), and the hydrolysis product was only inosine which is ineffective on cells, this Ap4A effect was not due to Ap4A hydrolysis in ATP and adenosine monophosphate (AMP). A mixture of Ap4A and ATP elicited only partial additive effects on SLPI secretion. ADP was shown to be a potent antagonist of ATP and Ap4A receptors, with IC(50)s of 0.8 and 2 microM, respectively. 2-MeS-ATP also showed antagonistic properties with IC(50)s of 20 and 30 microM for ATP- and Ap4A-receptors, respectively. Single cell intracellular calcium ([Ca(2+)](i)) measurements showed similar transient increases of [Ca(2+)](i) after ATP or Ap4A challenges. ATP desensitized the cell [Ca(2+)](i) responses to ATP and Ap4A, and Ap4A also desensitized the cell response to Ap4A. Nevertheless, Ap4A did not desensitize the cell [Ca(2+)](i) responses to ATP. In conclusion, both P2Y2-ATP-receptors and Ap4A-P2D-receptors seem to be present in tracheal gland cells. Ap4A may only bind to P2D-receptors whilst ATP may bind to both Ap4A- and ATP-receptors.

Chronic nicotine exposure selectively activates a carrier-mediated release of endogenous glutamate and aspartate from rat hippocampal synaptosomes.

PubMed

Marchi, Mario; Zappettini, Stefania; Olivero, Guendalina; Pittaluga, Anna; Grilli, Massimo

2012-05-01

The effect of chronic nicotine treatment on the release of endogenous glutamate (GLU), aspartate (ASP) and GABA evoked in vitro by KCl, 4-aminopyridine (4AP) and nicotinic agonists in synaptosomes of rat hippocampus was investigated. Rats were chronically administered with nicotine bitartrate or saline vehicle each for 14 days using osmotic mini-pumps. Hippocampal synaptosomes were stimulated with KCl, 4AP, nicotine or with choline (Ch) and 5-iodo-A-85380 dihydrochloride (5IA85380). The GLU and ASP overflow evoked by Ch, nicotine, KCl and 4AP were increased in treated animals while the nicotine-evoked GABA overflow was reduced and that evoked by Ch, KCl and 4AP was unaffected. The 5IA85380-evoked overflow of the three aminoacids (AAs) was always reduced. The increase of ASP and GLU overflow evoked by KCl, 4AP or Ch was blocked by dl-threo-β-benzyloxyaspartic acid (dl-TBOA), a carrier transporter inhibitor, and by inhibitors of the Na(+)/Ca(2+) exchangers 2-[[4-[(4-nitrophenyl)methoxy]phenyl]methyl]-4-thiazolidinecarboxylic acid ethyl ester (SN-6) and 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate (KB-R7943). In conclusion long-term nicotine treatment may selectively increase GLU and ASP overflow elicited by KCl, 4AP and Ch through the activation of a carrier-mediated release mechanism and completely abolished the stimulatory effects of α4β2 nAChRs which modulate the release of all the three AA. Copyright © 2012 Elsevier Ltd. All rights reserved.

Transport and metabolism of MitoQ10, a mitochondria-targeted antioxidant, in Caco-2 cell monolayers.

PubMed

Li, Yan; Fawcett, J Paul; Zhang, Hu; Tucker, Ian G

2007-04-01

Mitoquinone (MitoQ(10) mesylate) is a mitochondria-targeted antioxidant formulated for oral administration in the treatment of neurodegenerative diseases. We have investigated the absorption and metabolism of MitoQ(10) in Caco-2 cell monolayers. The intracellular accumulation of MitoQ(10) was 18-41% of the total amount of MitoQ(10) added. Some of the intracellular MitoQ(10) was reduced to mitoquinol and subsequently metabolized to glucuronide and sulfate conjugates. Transport of MitoQ(10) was polarized with the apparent permeability (P(app)) from basolateral (BL) to apical (AP) (P(appBL-->AP)) being >2.5-fold the P(app) from apical to basolateral (P(appAP-->BL)). In the presence of 4% bovine serum albumin on the basolateral side, the P(appAP-->BL) value increased 7-fold compared with control. The P(appBL-->AP) value decreased by 26, 31 and 61% in the presence of verapamil 100 microM, ciclosporin 10 and 30 microM, respectively, whereas the P(appAP-->BL) value increased 71% in the presence of ciclosporin 30 microM. Apical efflux of mitoquinol sulfate and mitoquinol glucuronide conjugates was significantly decreased by ciclosporin 30 microM and the breast cancer receptor protein (BCRP) inhibitor, reserpine 25 microM, respectively. These results suggested that the bioavailability of MitoQ(10) may be limited by intracellular metabolism and the action of P-glycoprotein and BCRP. However, the dramatic increase in absorptive P(app) in the presence of bovine serum albumin on the receiver side suggests these barrier functions may be less significant in-vivo.

Space Environment Effects: Low-Altitude Trapped Radiation Model

NASA Technical Reports Server (NTRS)

Huston, S. L.; Pfitzer, K. A.

1998-01-01

Accurate models of the Earth's trapped energetic proton environment are required for both piloted and robotic space missions. For piloted missions, the concern is mainly total dose to the astronauts, particularly in long-duration missions and during extravehicular activity (EVA). As astronomical and remote-sensing detectors become more sensitive, the proton flux can induce unwanted backgrounds in these instruments. Due to this unwanted background, the following description details the development of a new model for the low-trapped proton environment. The model is based on nearly 20 years of data from the TIRO/NOAA weather satellites. The model, which has been designated NOAAPRO (for NOAA protons), predicts the integral omnidirectional proton flux in three energy ranges: >16, >36, and >80 MeV. It contains a true solar cycle variation and accounts for the secular variation in the Earth's magnetic field. It also extends to lower values of the magnetic L parameter than does AP8. Thus, the model addresses the major shortcomings of AP8.

P4-ATPase Requirement for AP-1/Clathrin Function in Protein Transport from the trans-Golgi Network and Early Endosomes

PubMed Central

Liu, Ke; Surendhran, Kavitha; Nothwehr, Steven F.

2008-01-01

Drs2p is a resident type 4 P-type ATPase (P4-ATPase) and potential phospholipid translocase of the trans-Golgi network (TGN) where it has been implicated in clathrin function. However, precise protein transport pathways requiring Drs2p and how it contributes to clathrin-coated vesicle budding remain unclear. Here we show a functional codependence between Drs2p and the AP-1 clathrin adaptor in protein sorting at the TGN and early endosomes of Saccharomyces cerevisiae. Genetic criteria indicate that Drs2p and AP-1 operate in the same pathway and that AP-1 requires Drs2p for function. In addition, we show that loss of AP-1 markedly increases Drs2p trafficking to the plasma membrane, but does not perturb retrieval of Drs2p from the early endosome back to the TGN. Thus AP-1 is required at the TGN to sort Drs2p out of the exocytic pathway, presumably for delivery to the early endosome. Moreover, a conditional allele that inactivates Drs2p phospholipid translocase (flippase) activity disrupts its own transport in this AP-1 pathway. Drs2p physically interacts with AP-1; however, AP-1 and clathrin are both recruited normally to the TGN in drs2Δ cells. These results imply that Drs2p acts independently of coat recruitment to facilitate AP-1/clathrin-coated vesicle budding from the TGN. PMID:18508916

Selenizing astragalus polysaccharide attenuates PCV2 replication promotion caused by oxidative stress through autophagy inhibition via PI3K/AKT activation.

PubMed

Liu, Dandan; Xu, Jing; Qian, Gang; Hamid, Mohammed; Gan, Fang; Chen, Xingxiang; Huang, Kehe

2018-03-01

Our previous studies have shown that oxidative stress could promote the porcine circovirus type 2 (PCV2) replication, and astragalus polysaccharide (APS)/selenium could suppress PCV2 replication. However, whether selenizing astragalus polysaccharide (sAPS) provides protection against oxidative stress-induced PCV2 replication promotion and the mechanism involved remain unclear. The present study aimed to explore the mechanism of the PCV2 replication promotion induced by oxidative stress and a novel pharmacotherapeutic approach involving the regulation of autophagy of sAPS. Our results showed that H 2 O 2 promoted PCV2 replication via enhancing autophagy by using 3-methyladenine (3-MA) and autophagy-related gene 5 (ATG5) knockdown. Sodium selenite, APS, the mixture of sodium selenite and APS, and sAPS significantly inhibited H 2 O 2 -induced PCV2 replication promotion, respectively. Among these, sAPS exerted maximal inhibitory effect. sAPS could also significantly inhibit autophagy activated by H 2 O 2 and increase the Akt and mTOR phosphorylation. Moreover, LY294002, the specific phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) inhibitor, significantly alleviated the effects of sAPS on autophagy and PCV2 replication. Taken together, we conclude that H 2 O 2 promotes PCV2 replication by inducing autophagy and sAPS attenuates the PCV2 replication promotion through autophagy inhibition via PI3K/AKT activation. Copyright © 2017 Elsevier B.V. All rights reserved.

Health in All Policies in South Australia: what has supported early implementation?

PubMed

Delany, Toni; Lawless, Angela; Baum, Frances; Popay, Jennie; Jones, Laura; McDermott, Dennis; Harris, Elizabeth; Broderick, Danny; Marmot, Michael

2016-12-01

Health in All Policies (HiAP) is a policy development approach that facilitates intersectoral responses to addressing the social determinants of health and health equity whilst, at the same time, contributing to policy priorities across the various sectors of government. Given that different models of HiAP have been implemented in at least 16 countries, there is increasing interest in how its effectiveness can be optimized. Much of the existing literature on HiAP remains descriptive, however, and lacks critical, empirically informed analyses of the elements that support implementation. Furthermore, literature on HiAP, and intersectoral action more generally, provides little detail on the practical workings of policy collaborations. This paper contributes empirical findings from a multi-method study of HiAP implementation in South Australia (SA) between 2007 and 2013. It considers the views of public servants and presents analysis of elements that have supported, and impeded, implementation of HiAP in SA. We found that HiAP has been implemented in SA using a combination of interrelated elements. The operation of these elements has provided a strong foundation, which suggests the potential for HiAP to extend beyond being an isolated strategy, to form a more integrated and systemic mechanism of policy-making. We conclude with learnings from the SA experience of HiAP implementation to inform the ongoing development and implementation of HiAP in SA and internationally. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cerebral infarction in the left hemisphere compared with the right hemisphere increases the risk of aspiration pneumonia.

PubMed

Yamamoto, Keiichi; Koh, Hideo; Shimada, Hiroyuki; Takeuchi, Jun; Yamakawa, Yoshihiro; Kawamura, Mayumi; Miki, Takami

2014-12-01

Aspiration pneumonia (AP) following cerebral infarction (CI) has been considered as one of its most serious complications. Nevertheless, there are no reports on the association between the type or location of CI and the incidence of AP. In addition, the association between dysphagia, which leads to aspiration, and the type or location of CI has never been investigated. Therefore we hypothesized that the laterality of CI affects the development of both dysphagia and AP. We performed a retrospective cohort study to examine the association between the laterality of CI and the incidence of dysphagia and AP in 133 patients. AP was found in 6.0% of the group with left CI and in 0.8% of the group with right CI. A univariate logistic regression analysis revealed that left CI was a significant predictor of AP (hazard ratio, 8.81; 95% confidence interval, 1.07-72.59; p = 0.043). Left CI was a significant predictor of AP even after adjusting for age, sex, CI type, or presence of diabetes mellitus. In addition, although the frequency of dysphagia as the direct cause of AP did not differ according to laterality, the frequency of AP that ensued from dysphagia in the left CI group was greater than that observed in the right CI group. The group with left CI from the motor cortex to the internal capsule complicated by dysphagia exhibited a high risk of AP.

Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependent.

PubMed

Idelevich, Anna; Sato, Kazusa; Nagano, Kenichi; Rowe, Glenn; Gori, Francesca; Baron, Roland

2018-06-01

In the brain, the ventral hypothalamus (VHT) regulates energy and bone metabolism. Whether this regulation uses the same or different neuronal circuits is unknown. Alteration of AP1 signaling in the VHT increases energy expenditure, glucose utilization, and bone density, yet the specific neurons responsible for each or all of these phenotypes are not identified. Using neuron-specific, genetically targeted AP1 alterations as a tool in adult mice, we found that agouti-related peptide-expressing (AgRP-expressing) or proopiomelanocortin-expressing (POMC-expressing) neurons, predominantly present in the arcuate nucleus (ARC) within the VHT, stimulate whole-body energy expenditure, glucose utilization, and bone formation and density, although their effects on bone resorption differed. In contrast, AP1 alterations in steroidogenic factor 1-expressing (SF1-expressing) neurons, present in the ventromedial hypothalamus (VMH), increase energy but decrease bone density, suggesting that these effects are independent. Altered AP1 signaling also increased the level of the neuromediator galanin in the hypothalamus. Global galanin deletion (VHT galanin silencing using shRNA) or pharmacological galanin receptor blockade counteracted the observed effects on energy and bone. Thus, AP1 antagonism reveals that AgRP- and POMC-expressing neurons can stimulate body metabolism and increase bone density, with galanin acting as a central downstream effector. The results obtained with SF1-expressing neurons, however, indicate that bone homeostasis is not always dictated by the global energy status, and vice versa.

Mechanisms of anterior-posterior stability of the knee joint under load-bearing.

PubMed

Reynolds, Ryan J; Walker, Peter S; Buza, John

2017-05-24

The anterior-posterior (AP) stability of the knee is an important aspect of functional performance. Studies have shown that the stability increases when compressive loads are applied, as indicated by reduced laxity, but the mechanism has not been fully explained. A test rig was designed which applied combinations of AP shear and compressive forces, and measured the AP displacements relative to the neutral position. Five knees were evaluated at compressive loads of 0, 250, 500, and 750N, with the knee at 15° flexion. At each load, three cycles of shear force at ±100N were applied. For the intact knee under load, the posterior tibial displacement was close to zero, due to the upward slope of the anterior medial tibial surface. The soft tissues were then resected in sequence to determine their role in AP laxity. After anterior cruciate ligament (ACL) resection, the anterior tibial displacement increased significantly even under load, highlighting its importance in stability. Meniscal resection further increased displacement but also the vertical displacement increased, implying the meniscus was providing a buffering effect. The PCL had no effect on any of the displacements under load. Plowing cartilage deformation and surface friction were negligible. This work highlighted the particular importance of the upward slope of the anterior medial tibial surface and the ACL to AP knee stability under load. The results are relevant to the design of total knees which reproduce anatomic knee stability behavior. Copyright © 2017. Published by Elsevier Ltd.

Hepatitis C virus core protein potentiates proangiogenic activity of hepatocellular carcinoma cells.

PubMed

Shao, Yu-Yun; Hsieh, Min-Shu; Wang, Han-Yu; Li, Yong-Shi; Lin, Hang; Hsu, Hung-Wei; Huang, Chung-Yi; Hsu, Chih-Hung; Cheng, Ann-Lii

2017-10-17

Increased angiogenic activity has been demonstrated in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), but the mechanism was unclear. To study the role of HCV core protein, we used tube formation and Matrigel plug assays to assess the proangiogenic activity of an HCC cell line, HuH7, and 2 of its stable clones-HuH7-core-high and HuH7-core-low, with high and low HCV core protein expression, respectively. In both assays, HuH7-core-high and HuH7-core-low cells dose-dependently induced stronger angiogenesis than control cells. HuH7 cells with HCV core protein expression showed increased mRNA and protein expression of vascular endothelial growth factor (VEGF). VEGF inhibition by bevacizumab reduced the proangiogenic activity of HuH7-core-high cells. The promotor region of VEGF contains the binding site of activator protein-1 (AP-1). Compared with controls, HuH7-core-high cells had an increased AP-1 activity and nuclear localization of phospho-c-jun. AP-1 inhibition using either RNA knockdown or AP-1 inhibitors reduced the VEGF mRNA expression and the proangiogenic activity of HuH7-core-high cells. Among 131 tissue samples from HCC patients, HCV-related HCC revealed stronger VEGF expression than did hepatitis B virus-related HCC. In conclusion, increased VEGF expression through AP-1 activation is a crucial mechanism underlying the proangiogenic activity of the HCV core protein in HCC cells.

Hepatitis C virus core protein potentiates proangiogenic activity of hepatocellular carcinoma cells

PubMed Central

Shao, Yu-Yun; Hsieh, Min-Shu; Wang, Han-Yu; Li, Yong-Shi; Lin, Hang; Hsu, Hung-Wei; Huang, Chung-Yi; Hsu, Chih-Hung; Cheng, Ann-Lii

2017-01-01

Increased angiogenic activity has been demonstrated in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), but the mechanism was unclear. To study the role of HCV core protein, we used tube formation and Matrigel plug assays to assess the proangiogenic activity of an HCC cell line, HuH7, and 2 of its stable clones—HuH7-core-high and HuH7-core-low, with high and low HCV core protein expression, respectively. In both assays, HuH7-core-high and HuH7-core-low cells dose-dependently induced stronger angiogenesis than control cells. HuH7 cells with HCV core protein expression showed increased mRNA and protein expression of vascular endothelial growth factor (VEGF). VEGF inhibition by bevacizumab reduced the proangiogenic activity of HuH7-core-high cells. The promotor region of VEGF contains the binding site of activator protein-1 (AP-1). Compared with controls, HuH7-core-high cells had an increased AP-1 activity and nuclear localization of phospho-c-jun. AP-1 inhibition using either RNA knockdown or AP-1 inhibitors reduced the VEGF mRNA expression and the proangiogenic activity of HuH7-core-high cells. Among 131 tissue samples from HCC patients, HCV-related HCC revealed stronger VEGF expression than did hepatitis B virus-related HCC. In conclusion, increased VEGF expression through AP-1 activation is a crucial mechanism underlying the proangiogenic activity of the HCV core protein in HCC cells. PMID:29156827

Tomsk Cardiology Center program on lasers in cardiovascular: first results

NASA Astrophysics Data System (ADS)

Gordov, Eugeni P.; Karpov, Rostislav S.; Dudko, Victor A.; Shipulin, Vladimir M.

1994-12-01

Recent progress in biomedical optics resulted in increased activity in this area at a number of different centers. Reported are the first results of the program directed to incorporate at Tomsk Cardiology Center experience gained in Tomsk optical profile research institutions in areas of light-matter interaction, high resolution spectroscopy, laser physics and relevant software and their usage in cardiac therapy, surgery, and diagnostics. To coordinate research work in this direction the special unit-laboratory of laser medicine is organized at the Center. Laboratory activity goes in the following directions: study of spectral properties of vessel walls in norm and atherosclerosis, comparative study of different wavelength laser radiation action on normal and atherosclerotically damaged tissues, novel approach to intravascular imaging, and usage of high sensitive laser spectroscopy for early diagnosis of cardiac diseases. The spectroscopic study of AP and normal tissue is aimed at understanding of differences in internal energy structures and ways of energy migration which are of critical importance for reaching selective laser action on normal and deceased tissues. To compare thermal, mechanical, and photo-chemical variations of tissues caused by laser radiation the XeCl excimer laser with Raman shifting cell and Nd:YAG laser with second, third, and fourth harmonic converters are employed. Fine influence of pulse duration, intensity, and repetition rates on AP removal is considered in laboratory experiments with vessel samples. Preliminary results on theoretical consideration for determination of spectroscopically detectable markers of some cardiac diseases are reported as well.

Maximum heart rate in brown trout (Salmo trutta fario) is not limited by firing rate of pacemaker cells.

PubMed

Haverinen, Jaakko; Abramochkin, Denis V; Kamkin, Andre; Vornanen, Matti

2017-02-01

Temperature-induced changes in cardiac output (Q̇) in fish are largely dependent on thermal modulation of heart rate (f H ), and at high temperatures Q̇ collapses due to heat-dependent depression of f H This study tests the hypothesis that firing rate of sinoatrial pacemaker cells sets the upper thermal limit of f H in vivo. To this end, temperature dependence of action potential (AP) frequency of enzymatically isolated pacemaker cells (pacemaker rate, f PM ), spontaneous beating rate of isolated sinoatrial preparations (f SA ), and in vivo f H of the cold-acclimated (4°C) brown trout (Salmo trutta fario) were compared under acute thermal challenges. With rising temperature, f PM steadily increased because of the acceleration of diastolic depolarization and shortening of AP duration up to the break point temperature (T BP ) of 24.0 ± 0.37°C, at which point the electrical activity abruptly ceased. The maximum f PM at T BP was much higher [193 ± 21.0 beats per minute (bpm)] than the peak f SA (94.3 ± 6.0 bpm at 24.1°C) or peak f H (76.7 ± 2.4 at 15.7 ± 0.82°C) (P < 0.05). These findings strongly suggest that the frequency generator of the sinoatrial pacemaker cells does not limit f H at high temperatures in the brown trout in vivo. Copyright © 2017 the American Physiological Society.

Diadenosine polyphosphates induce intracellular Ca2+ mobilization in human neutrophils via a pertussis toxin sensitive G-protein.

PubMed Central

Gasmi, L; McLennan, A G; Edwards, S W

1997-01-01

The diadenosine polyphosphates diadenosine 5',5"'-P1,P3-triphosphate (Ap3A), diadenosine 5',5"'-P1,P4-tetraphosphate (Ap4A), diadenosine 5',5"'-P1,P5-pentaphosphate (Ap5A) and diadenosine 5',5"'-P1,P6-hexaphosphate (Ap6A) all stimulated increases in intracellular Ca2+ in human neutrophils. Maximal increases in intracellular Ca2+ of 650 nM were obtained at dinucleotide concentrations of 500-700 microM. These increases in intracellular, Ca2+ were completely abolished by pre-treatment of the neutrophils with pertussis toxin and were hardly affected when the extracellular buffer was devoid of Ca2+. On the other hand, adenosine triphosphate (ATP) could stimulate much greater increases in intracellular Ca2+ (up to 1.1 microM) at much lower concentrations (half maximal responses obtained at around 5 microM ATP). Receptor de-sensitization experiments indicate that human neutrophils may possess two types of P2-purinoceptors. The first of these may bind ATP (but not the dinucleotides) with high affinity whilst the second may bind the dinucleotides with lower affinity and also bind ATP. PMID:9038726

[Cloning, subcellular localization, and heterologous expression of ApNAC1 gene from Andrographis paniculata].

PubMed

Wang, Jian; Qi, Meng-Die; Guo, Juan; Shen, Ye; Lin, Hui-Xin; Huang, Lu-Qi

2017-03-01

Andrographis paniculata is widely used as medicinal herb in China for a long time and andrographolide is its main medicinal constituent. To investigate the underlying andrographolide biosynthesis mechanisms, RNA-seq for A. paniculata leaves with MeJA treatment was performed. In A. paniculata transcriptomic data, the expression pattern of one member of NAC transcription factor family (ApNAC1) matched with andrographolide accumulation. The coding sequence of ApNAC1 was cloned by RT-PCR, and GenBank accession number was KY196416. The analysis of bioinformatics showed that the gene encodes a peptide of 323 amino acids, with a predicted relative molecular weight of 35.9 kDa and isoelectric point of 6.14. To confirm the subcellular localization, ApNAC1-GFP was transiently expressed in A. paniculata protoplast. The results indicated that ApNAC1 is a nucleus-localized protein. The analysis of real-time quantitative PCR revealed that ApNAC1 gene predominantly expresses in leaves. Compared with control sample, its expression abundance sharply increased with methyl jasmonate treatment. Based on its expression pattern, ApNAC1 gene might involve in andrographolide biosynthesis. ApNAC1 was heterologously expressed in Escherichia coli and recombinant protein was purified by Ni-NTA agarose. Further study will help us to understand the function of ApNAC1 in andrographolide biosynthesis. Copyright© by the Chinese Pharmaceutical Association.

Contractile activity of ATP and diadenosine tetraphosphate on urinary bladder in the rats: role of superoxide anion and urothelium.

PubMed

Khattab, M M; Al-Hrasen, M N

2006-04-01

Both ATP and diadenosine tetraphosphate (AP(4)A) produced a dose-dependent contraction of rat isolated urinary bladder rings. The AP(4)A dose-response curve was to the left of that of ATP, and the maximum response was greater than that produced by ATP. Mechanical removal of the urothelium increased the contractile response to ATP by between 53% and 71%, and that to AP(4)A by 42% (at highest AP(4)A concentration) to 68% at lower concentration. Inhibition of Cu/Zn superoxide dismutase with diethylthiocarbamate (DETCA, 5 mm) significantly reduced the ATP-evoked contraction by 31% (at high ATP concentration) to 40% at low ATP concentration. Similarly, the AP(4)A-induced contractions were significantly decreased by 27% at low AP(4)A level to 38% at higher concentrations. Induction of exogenous superoxide anion stress by the use of the superoxide anion generator, pyrogallol (0.5 mm), significantly decreased both ATP- and AP(4)A-induced contractions of the rat urinary bladder over the whole dose range. Contractile responses to ATP decreased by 36-40%, and those to AP(4)A by 44-49%. In conclusion, the urinary bladder urothelium exerts an inhibitory control over the purinergic contractility produced by adenine mononucleotides and dinucleotides. Superoxide anion stress, whether endogenous or exogenous, attenuates the ATP-induced as well as AP(4)A-induced contractility.

Inhibitors of the Diadenosine Tetraphosphate Phosphorylase Rv2613c of Mycobacterium tuberculosis.

PubMed

Götz, Kathrin H; Hacker, Stephan M; Mayer, Daniel; Dürig, Jan-Niklas; Stenger, Steffen; Marx, Andreas

2017-10-20

The intracellular concentration of diadenosine tetraphospate (Ap 4 A) increases upon exposure to stress conditions. Despite being discovered over 50 years ago, the cellular functions of Ap 4 A are still enigmatic. If and how the varied Ap 4 A is a signal and involved in the signaling pathways leading to an appropriate cellular response remain to be discovered. Because the turnover of Ap 4 A by Ap 4 A cleaving enzymes is rapid, small molecule inhibitors for these enzymes would provide tools for the more detailed study of the role of Ap 4 A. Here, we describe the development of a high-throughput screening assay based on a fluorogenic Ap 4 A substrate for the identification and optimization of small molecule inhibitors for Ap 4 A cleaving enzymes. As proof-of-concept we screened a library of over 42 000 compounds toward their inhibitory activity against the Ap 4 A phosphorylase (Rv2613c) of Mycobacterium tuberculosis (Mtb). A sulfanylacrylonitril derivative with an IC 50 of 260 ± 50 nM in vitro was identified. Multiple derivatives were synthesized to further optimize their properties with respect to their in vitro IC 50 values and their cytotoxicity against human cells (HeLa). In addition, we selected two hits to study their antimycobacterial activity against virulent Mtb to show that they might be candidates for further development of antimycobacterial agents against multidrug-resistant Mtb.

Chinese Herbal Medicines Attenuate Acute Pancreatitis: Pharmacological Activities and Mechanisms

PubMed Central

Xiang, Hong; Zhang, Qingkai; Qi, Bing; Tao, Xufeng; Xia, Shilin; Song, Huiyi; Qu, Jialin; Shang, Dong

2017-01-01

Acute pancreatitis (AP) is a commonly occurring gastrointestinal disorder. An increase in the annual incidence of AP has been observed, and it causes acute hospitalization and high mortality. The diagnosis and treatment guidelines for AP recommend conservative medical treatments focused on reducing pancreatic secretion and secondary injury, as a primary therapeutic approach. Unfortunately, the existing treatment options have limited impact on the incidence and severity of AP due to the complex and multifaceted pathological process of this disease. In recent decades, Chinese herbal medicines (CHMs) have been used as efficient therapeutic agents to attenuate AP in Asian countries. Despite early cell culture, animal models, and clinical trials, CHMs are capable of interacting with numerous molecular targets participating in the pathogenesis of AP; however, comprehensive, up-to-date communication in this field is not yet available. This review focuses on the pharmacological activities of CHMs against AP in vitro and in vivo and the underlying mechanisms. A computational prediction of few selected and promising plant-derived molecules (emodin, baicalin, resveratrol, curcumin, ligustrazine, and honokiol) to target numerous proteins or networks involved in AP was initially established based on a network pharmacology simulation. Moreover, we also summarized some potential toxic natural products for pancreas in order to more safe and reasonable medication. These breakthrough findings may have important implications for innovative drug research and the future development of treatments for AP. PMID:28487653

Computer-controlled closed-loop drug infusion system for automated hemodynamic resuscitation in endotoxin-induced shock.

PubMed

Uemura, Kazunori; Kawada, Toru; Zheng, Can; Li, Meihua; Sugimachi, Masaru

2017-10-23

Hemodynamic resuscitation in septic shock requires aggressive fluid replacement and appropriate use of vasopressors to optimize arterial pressure (AP) and cardiac output (CO). Because responses to these drugs vary between patients and within patient over time, strict monitoring of patient condition and repetitive adjustment of drug dose are required. This task is time and labor consuming, and is associated with poor adherence to resuscitation guidelines. To overcome this issue, we developed a computer-controlled closed-loop drug infusion system for automated hemodynamic resuscitation in septic shock, and evaluated the performance of the system in a canine model of endotoxin shock. Our system monitors AP, CO and central venous pressure, and computes arterial resistance (R), stressed blood volume (V) and Frank-Starling slope of left ventricle (S). The system controls R with noradrenaline (NA), and V with Ringer's acetate solution (RiA), thereby controlling AP and CO. In 4 dogs, AP and CO were measured invasively. In another 4 dogs, AP and CO were measured less invasively using clinically acceptable modalities, aiming to make the system clinically feasible. In all 8 dogs, endotoxin shock was induced by injecting Escherichia coli lipopolysaccharide, which significantly decreased AP from 95 (91-108) to 43 (39-45) mmHg, and CO from 112 (104-142) to 62 (51-73) ml·min -1 ·kg -1 . The system was then connected to the dogs, and activated. System performance was observed over a period of 4 h. Our system immediately started infusions of NA and RiA. Within 40 min, RiA increased V to target level, and NA maintained R at target level, while S was concomitantly increased. These resulted in restoration of AP to 70 (69-71) mmHg and CO to 130 (125-138) ml·min -1 ·kg -1 . Median of absolute performance error, an index of precision of control, was small in AP [2.5 (2.1-4.5) %] and CO [2.4 (1.4-5.5) %], which were not increased even when the variables were measured less invasively. In a canine model of endotoxin shock, our system automatically improved and maintained AP and CO at their target values with small performance error. Our system is potentially an attractive clinical tool for rescuing patients with septic shock.

[Inhibitory effect and the mechanism of Astragalus polysaccharide combined with cisplatin on growth of inplanted Lewis lung carcinoma in mice].

PubMed

Zhuang, Mengjie; Liu, Dan; Chen, Yanwen; Ming, Haixia; Li, Yang

2017-04-01

Objective To observe the effect of Astragalus polysaccharides (APS) combined with cisplatin (DDP) on the expressions of cytochrome C (CytC) and high temperature required serine protease A2 (Omi/HtrA2) in the mice with Lewis lung carcinoma (LLC) transplantated tumors. Methods Ninty C57BL/6J mice were randomly divided into normal control group, model group, and (50, 100, 200) μg/mL APS groups, 6 mg/kg DDP group, 3 mg/kg DDP combined with (50, 100, 200) μg/mL APS groups. Each group included 10 mice. Except the mice in the normal group, the rest mice were inoculated subcutaneously with LLC cells (1×10 7 mL) at the right fore axillary fossa to establish tumor-bearing mouse models. In the second day of building models, the mice in the treatment group were given intraperitoneal injection of 0.3 mL of the drug. DDP was given once a week, and the other drugs once a day. The mice in the normal group and the model group were administrated the same amount of saline injection for continuous 20 days. All mice were killed at the 21st day. The pathological changes of tumor tissues were observed by HE staining. The expressions and location of CytC and Omi/HtrA2 proteins in the transplanted tumor tissues were detected by immunohistochemical staining and image analysis. Results The mass of tumor decreased in the mice of (100, 200) μg/mL APS group and 3 mg/kg DDP combined with (100, 200) μg/mL APS group. Compared with the model group, the necrosis of tumor tissues in 200 μg/mL APS combined with 3 mg/kg DDP group was the most obvious. The expressions of CytC and Omi/HtrA2 increased in the treatment groups, and the increase was the most remarkable in 200 μg/mL APS combined with 3 mg/kg DDP group. Conclusion APS and APS combined with DDP can restrain the growth of Lewis Lung cancer in C57BL/6J mice, which may be related to the increased expressions of CytC and Omi/HtrA2.

Emerging Gastrointestinal and Liver Diseases in Asia Pacific: Implications to Health Care in the Region (World Gastroenterology Organization: Asian Pacific Association of Gastroenterology Distinguished Global Lecture 2015).

PubMed

Goh, Khean-Lee

2017-07-01

Colorectal cancer (CRC), gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), and nonalcoholic fatty liver disease are considered important emerging diseases in the Asia Pacific (AP) region. The incidence rate of CRC is the highest among gastrointestinal cancers in the region surpassing that of gastric cancer. However, population CRC screening is limited by availability of adequate health resources and financing. GERD is a highly prevalent disease in AP with the prevalence of GERD symptoms and reflux esophagitis reported to be increasing. The usage of proton pump inhibitors has also been reported to be high. The incidence and prevalence of IBD is not as high as in the west but is now an increasingly recognizable disease in the AP region. Being a complicated disease, IBD will pose a huge financial burden with the increasing use of expensive biological drugs. In tandem with the exponential increase in obesity and diabetes mellitus in AP, nonalcoholic fatty liver disease will become the most important liver disease in the region in the coming years. These emerging diseases reflect the continued fast-paced socioeconomic development in the region with marked lifestyle changes and increasing affluence.

X-ray optics simulation and beamline design for the APS upgrade

NASA Astrophysics Data System (ADS)

Shi, Xianbo; Reininger, Ruben; Harder, Ross; Haeffner, Dean

2017-08-01

The upgrade of the Advanced Photon Source (APS) to a Multi-Bend Achromat (MBA) will increase the brightness of the APS by between two and three orders of magnitude. The APS upgrade (APS-U) project includes a list of feature beamlines that will take full advantage of the new machine. Many of the existing beamlines will be also upgraded to profit from this significant machine enhancement. Optics simulations are essential in the design and optimization of these new and existing beamlines. In this contribution, the simulation tools used and developed at APS, ranging from analytical to numerical methods, are summarized. Three general optical layouts are compared in terms of their coherence control and focusing capabilities. The concept of zoom optics, where two sets of focusing elements (e.g., CRLs and KB mirrors) are used to provide variable beam sizes at a fixed focal plane, is optimized analytically. The effects of figure errors on the vertical spot size and on the local coherence along the vertical direction of the optimized design are investigated.

Fabrication and Physical Evaluation of Gelatin-Coated Carbonate Apatite Foam.

PubMed

Hara, Kanae; Fujisawa, Kenji; Nagai, Hirokazu; Takamaru, Natsumi; Ohe, Go; Tsuru, Kanji; Ishikawa, Kunio; Miyamoto, Youji

2016-08-23

Carbonate apatite (CO₃Ap) foam has gained much attention in recent years because of its ability to rapidly replace bone. However, its mechanical strength is extremely low for clinical use. In this study, to understand the potential of gelatin-reinforced CO₃Ap foam for bone replacement, CO₃Ap foam was reinforced with gelatin and the resulting physical characteristics were evaluated. The mechanical strength increased significantly with the gelatin reinforcement. The compressive strength of gelatin-free CO₃Ap foam was 74 kPa whereas that of the gelatin-reinforced CO₃Ap foam, fabricated using 30 mass % gelatin solution, was approximately 3 MPa. Heat treatment for crosslinking gelatin had little effect on the mechanical strength of the foam. The gelatin-reinforced foam did not maintain its shape when immersed in a saline solution as this promoted swelling of the gelatin; however, in the same conditions, the heat-treated gelatin-reinforced foam proved to be stable. It is concluded, therefore, that heat treatment is the key to the fabrication of stable gelatin-reinforced CO₃Ap foam.

Variable Action Potential Backpropagation during Tonic Firing and Low-Threshold Spike Bursts in Thalamocortical But Not Thalamic Reticular Nucleus Neurons.

PubMed

Connelly, William M; Crunelli, Vincenzo; Errington, Adam C

2017-05-24

Backpropagating action potentials (bAPs) are indispensable in dendritic signaling. Conflicting Ca 2+ -imaging data and an absence of dendritic recording data means that the extent of backpropagation in thalamocortical (TC) and thalamic reticular nucleus (TRN) neurons remains unknown. Because TRN neurons signal electrically through dendrodendritic gap junctions and possibly via chemical dendritic GABAergic synapses, as well as classical axonal GABA release, this lack of knowledge is problematic. To address this issue, we made two-photon targeted patch-clamp recordings from rat TC and TRN neuron dendrites to measure bAPs directly. These recordings reveal that "tonic"' and low-threshold-spike (LTS) "burst" APs in both cell types are always recorded first at the soma before backpropagating into the dendrites while undergoing substantial distance-dependent dendritic amplitude attenuation. In TC neurons, bAP attenuation strength varies according to firing mode. During LTS bursts, somatic AP half-width increases progressively with increasing spike number, allowing late-burst spikes to propagate more efficiently into the dendritic tree compared with spikes occurring at burst onset. Tonic spikes have similar somatic half-widths to late burst spikes and undergo similar dendritic attenuation. In contrast, in TRN neurons, AP properties are unchanged between LTS bursts and tonic firing and, as a result, distance-dependent dendritic attenuation remains consistent across different firing modes. Therefore, unlike LTS-associated global electrical and calcium signals, the spatial influence of bAP signaling in TC and TRN neurons is more restricted, with potentially important behavioral-state-dependent consequences for synaptic integration and plasticity in thalamic neurons. SIGNIFICANCE STATEMENT In most neurons, action potentials (APs) initiate in the axosomatic region and propagate into the dendritic tree to provide a retrograde signal that conveys information about the level of cellular output to the locations that receive most input: the dendrites. In thalamocortical and thalamic reticular nucleus neurons, the site of AP generation and the true extent of backpropagation remain unknown. Using patch-clamp recordings, this study measures dendritic propagation of APs directly in these neurons. In either cell type, high-frequency low-threshold spike burst or lower-frequency tonic APs undergo substantial voltage attenuation as they spread into the dendritic tree. Therefore, backpropagating spikes in these cells can only influence signaling in the proximal part of the dendritic tree. Copyright © 2017 Connelly et al.

Epidemiology and outcome of acute pancreatitis in end-stage renal disease dialysis patients: a 10-year national cohort study.

PubMed

Chen, Hung-Jui; Wang, Jhi-Joung; Tsay, Wen-Ing; Her, Shwu-Huey; Lin, Cheng-Heng; Chien, Chih-Chiang

2017-10-01

The objective of this study is to determine the incidence and severity of acute pancreatitis (AP) in patients with end-stage renal disease (ESRD) on dialysis and whether the dialysis modality [hemodialysis (HD) versus peritoneal dialysis (PD)] confers a higher risk for AP as well as complications or mortality related to AP. We analyzed national health insurance claims data of 67 078 ESRD patients initiating dialysis between 1999 and 2007 in Taiwan. All patients were followed up from the start of their dialysis to first AP diagnosis, death, end of dialysis or 31 December 2008. Cox proportional hazards models were used to identify risk factors. The cumulative incidence rates of AP were 0.6, 1.7, 2.6, 3.4 and 4% at 1, 3, 5, 7 and 9 years, respectively. ESRD patients on HD and PD had an AP incidence of 5.11 and 5.86 per 1000 person-years, respectively. Independent risk factors for AP in this population were being elderly, being female, having biliary stones or liver disease, and being on PD. Severe AP occurred in 44.9% of the HD patients and in 36% of the PD patients. Patients with AP on HD had a higher incidence of upper gastrointestinal (UGI) bleeding than those on PD (P = 0.002). In contrast, those with AP on PD had a higher incidence of need for total parenteral nutrition (TPN) support than those on HD (P = 0.072). Overall in-hospital mortality was 8.1%. The risk factors for mortality after an AP attack were male gender, increased age, AP severity, and the presence of diabetes mellitus or liver disease. ESRD patients on PD were at higher risk for AP than those on HD. HD patients with AP attacks had a greater incidence of UGI bleeding and PD patients with AP attacks a more frequent need for TPN support. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

HPV16 E6 regulates annexin 1 (ANXA1) protein expression in cervical carcinoma cell lines

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

Calmon, Marilia Freitas; Sichero, Laura; Boccardo, Enrique

Annexin 1 (ANXA1) is a substrate for E6AP mediated ubiquitylation. It has been hypothesized that HPV 16 E6 protein redirects E6AP away from ANXA1, increasing its stability and possibly contributing to viral pathogenesis. We analyzed ANXA1 expression in HPV-positive and negative cervical carcinoma-derived cells, in cells expressing HPV-16 oncogenes and in cells transduced with shRNA targeting E6AP. We observed that ANXA1 protein expression increased in HPV-16-positive tumor cells, in keratinocytes expressing HPV-16 E6wt (wild-type) or E6/E7 and C33 cells expressing HPV-16 E6wt. ANXA1 protein expression decreased in cells transfected with E6 Dicer-substrate RNAs (DsiRNA) and C33 cells cotransduced with HPV-16more » E6wt and E6AP shRNA. Moreover, colony number and proliferation rate decreased in HPV16-positive cells transduced with ANXA1 shRNA. We observed that in cells infected with HPV16, the E6 binds to E6AP to degrade p53 and upregulate ANXA1. We suggest that ANXA1 may play a role in HPV-mediated carcinogenesis. - Highlights: • ANXA1 upregulation requires the presence of E6 and E6AP and is dependent on E6 integrity. • E6 binds to E6AP to degrade p53 and upregulate ANXA1 in cells infected with HPV16. • ANXA1 plays a role in cell proliferation in HPV-positive cervical cells.« less

Grapefruit juice and its constituents augment colchicine intestinal absorption: potential hazardous interaction and the role of p-glycoprotein.

PubMed

Dahan, Arik; Amidon, Gordon L

2009-04-01

To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate. Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP-BL and BL-AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6'-7'-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined. The effect of GFJ on colchicine intestinal-permeability was then investigated in-situ in the rat perfusion model, in both jejunum and ileum. Colchicine exhibited 20-fold higher BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion, which was reduced by verapamil/quinidine. Colchicine AP-BL permeability was increased and BL-AP was decreased by GFJ in a concentration-dependent manner (IC(50) values of 0.75% and 0.46% respectively), suggesting inhibition of efflux transport, rather than metabolizing enzyme. Similar effects obtained following pre-experiment incubation with GFJ, even though the juice was not present throughout the transepithelial study. 6'-7'-Dihydroxybergamottin, naringin and naringenin displayed concentration-dependent inhibition on colchicine BL-AP secretion (IC(50) values of 90, 592 and 11.6 microM respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability. The data suggest that GFJ may augment colchicine oral bioavailability. Due to colchicine narrow therapeutic-index and severely toxic side-effects, awareness of this interaction is prudent.

Effect of Retraining Approach-Avoidance Tendencies on an Exercise Task: A Randomized Controlled Trial.

PubMed

Cheval, Boris; Sarrazin, Philippe; Pelletier, Luc; Friese, Malte

2016-12-01

Promoting regular physical activity (PA) and lessening sedentary behaviors (SB) constitute a public health priority. Recent evidence suggests that PA and SB are not only related to reflective processes (eg, behavioral intentions), but also to impulsive approach-avoidance tendencies (IAAT). This study aims to test the effect of a computerized IAAT intervention on an exercise task. Participants (N = 115) were randomly assigned to 1 of 3 experimental conditions, in which they were either trained to approach PA and avoid SB (ApPA-AvSB condition), to approach SB and avoid PA (ApSB-AvPA condition), or to approach and avoid PA and SB equally often (active control condition). The main outcome variable was the time spent carrying out a moderate intensity exercise task. IAAT toward PA decreased in the ApSB-AvPA condition, tended to increase in the ApPA-AvSB condition, and remained stable in the control condition. Most importantly, the ApPA-AvSB manipulation led to more time spent exercising than the ApSB-AvPA condition. Sensitivity analyses excluding individuals who were highly physically active further revealed that participants in the ApPA-AvSB condition spent more time exercising than participants in the control condition. These findings provide preliminary evidence that a single intervention session can successfully change impulsive approach tendencies toward PA and can increase the time devoted to an exercise task, especially among individuals who need to be more physically active. Potential implications for health behavior theories and behavior change interventions are outlined.

Sex differences in repolarization and slow delayed rectifier potassium current and their regulation by sympathetic stimulation in rabbits.

PubMed

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.

Adiponectin attenuates kidney injury and fibrosis in deoxycorticosterone acetate-salt and angiotensin II induced CKD mice.

PubMed

Tian, Mi; Tang, Li; Wu, Yuanyuan; Beddhu, Srinivasan; Huang, Yufeng

2018-06-06

Adiponectin (ApN) is a multifunctional adipokine. However high, rather than low, concentrations of ApN are unexpectedly found in patients with chronic kidney disease (CKD) via an as yet unknown mechanism and the role of ApN in CKD is unclear. We, herein, investigated the effect of ApN overexpression on the progressive renal injury resulted from deoxycorticosterone acetate-salt (DOCA) and angiotensin II (Ang-II) infusion using a transgenic, inducible ApN-overexpressing mouse model. Three groups of mice (wild type receiving no infusion (WT), WT and cyp1a1 ApN transgenic mice (ApN-Tg) receiving DOCA+Ang-II infusion (WT/DOCA+Ang-II and ApN-Tg/DOCA+Ang-II)) were assigned to receive a normal food containing 0.15% of the transgene inducer indol-3-carbinol (I3C) for 3 weeks. The I3C-induced ApN-Tg/DOCA+Ang-II mice, not the WT or WT/DOCA+Ang-II mice, overexpressing ApN in liver resulted in 3.15-fold increases in circulating ApN than non-transgenic controls. Of note, these transgenic mice receiving DOCA+Ang-II infusion were still hypertensive but had much less albuminuria and glomerular and tubulointerstitial fibrosis, which were associated with ameliorated podocyte injury determined by ameliorated podocyte loss and foot process effacement; and alleviated tubular injury determined by ameliorated mRNA overexpression of KIM-1 and NGAL and mRNA decreases of cubilin and megalin in tubular cells, compared with WT/DOCA+Ang-II mice. In addition, renal production of NF-kB-p65, NAPDH oxidase-2 and p47phox, and MAPK-related cellular proliferation, which were induced in WT/DOCA+Ang-II mice, were markedly reduced in ApN-Tg/DOCA+Ang-II mice. These results indicate that elevated ApN in CKD mouse model is renal protective. Enhancing adiponectin production or signaling may have therapeutic potential for CKD.

Inotropic effects of diadenosine tetraphosphate (AP4A) in human and animal cardiac preparations.

PubMed

Vahlensieck, U; Bokník, P; Gombosová, I; Huke, S; Knapp, J; Linck, B; Lüss, H; Müller, F U; Neumann, J; Deng, M C; Scheld, H H; Jankowski, H; Schlüter, H; Zidek, W; Zimmermann, N; Schmitz, W

1999-02-01

Diadenosine tetraphosphate (AP4A) is an endogenous compound and exerts diverse physiological effects in animal systems. However, the effects of AP4A on inotropy in ventricular cardiac preparations have not yet been studied. The effects of AP4A on force of contraction (FOC) were studied in isolated electrically driven guinea pig and human cardiac preparations. Furthermore, the effects of AP4A on L-type calcium current and [Ca]i were studied in isolated guinea pig ventricular myocytes. In guinea pig left atria, AP4A (0.1-100 microM) reduced FOC maximally by 36.5 +/- 4.3%. In guinea pig papillary muscles, AP4A (100 microM) alone was ineffective, but reduced isoproterenol-stimulated FOC maximally by 29.3 +/- 3.4%. The negative inotropic effects of AP4A in atria and papillary muscles were abolished by the A1-adenosine receptor antagonist 1, 3-dipropyl-cyclopentylxanthine. In guinea pig ventricular myocytes, AP4A (100 microM) attenuated isoproterenol-stimulated L-type calcium current and [Ca]i. In human atrial and ventricular preparations, AP4A (100 microM) alone increased FOC to 158.3 +/- 12.4% and 167.5 +/- 25.1%, respectively. These positive inotropic effects were abolished by the P2-purinoceptor antagonist suramin. On the other hand, AP4A (100 microM) reduced FOC by 27.2 +/- 7.4% in isoproterenol-stimulated human ventricular trabeculae. The latter effect was abolished by 1,3-dipropyl-cyclopentylxanthine. In summary, after beta adrenergic stimulation AP4A exerts negative inotropic effects in animal and human ventricular preparations via stimulation of A1-adenosine receptors. In contrast, AP4A alone can exert positive inotropic effects via P2-purinoceptors in human ventricular myocardium. Thus, P2-purinoceptor stimulation might be a new positive inotropic principle in the human myocardium.

Use and Characteristics of Antipsychotic/Methylphenidate Combination Therapy in Children and Adolescents with a Diagnosis of Attention-Deficit/Hyperactivity Disorder.

PubMed

Scholle, Oliver; Banaschewski, Tobias; Enders, Dirk; Garbe, Edeltraut; Riedel, Oliver

2018-05-16

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) frequently have comorbidities that are potential indications for antipsychotics (APs). Some studies have suggested that the combined use of methylphenidate (MPH) and APs is increasing in this population group. Longitudinal analyses and in-depth investigations on the substance level are lacking. This study aimed to estimate the cumulative proportion of concomitant AP/MPH use in children and adolescents with ADHD over a follow-up of up to 9 years and to describe patient characteristics stratified by specific AP drug. Based on claims data, concomitant AP/MPH use was identified among 67,595 children and adolescents with ADHD starting MPH treatment between 2005 and 2013. Characteristics and diagnoses-including those indicating appropriateness of AP use according to approved indications and/or guidelines-were examined at the time of first AP/MPH combination therapy. In addition, subsequent use of AP/MPH combination therapy was evaluated. The cumulative proportion of individuals with any AP/MPH combination therapy rose to over 6% within 9 years after initiating MPH. The most frequent APs first used in combination with MPH were risperidone (72%), pipamperone (15%), and tiapride (8%). Percentages of psychiatric hospitalization in the year preceding the first combination therapy with MPH were 33%, 43%, and 19%, respectively. The proportion of individuals with potentially appropriate use was high (>72%) in risperidone/MPH and tiapride/MPH and low (15%) in pipamperone/MPH combination users. Conduct disorders and tic disorders were frequent in users who were prescribed MPH with risperidone and tiapride, respectively. One-quarter of patients with AP/MPH combination therapy were one-time-only combination users. Our study suggests that a considerable proportion of children and adolescents with ADHD receive MPH in combination with APs and that this is a factor not only during the first years of MPH treatment. ADHD guidelines should specify algorithms concerning the use of AP medication.

Baseline grey matter volume of non-transitioned "ultra high risk" for psychosis individuals with and without attenuated psychotic symptoms at long-term follow-up.

PubMed

Cropley, Vanessa L; Lin, Ashleigh; Nelson, Barnaby; Reniers, Renate L E P; Yung, Alison R; Bartholomeusz, Cali F; Klauser, Paul; Velakoulis, Dennis; McGorry, Patrick; Wood, Stephen J; Pantelis, Christos

2016-06-01

Two thirds of individuals identified as ultra-high risk (UHR) for psychosis do not transition to psychosis over the medium to long-term (non-transition; UHR-NT). Nevertheless, many of these individuals have persistent attenuated psychotic symptoms (APS). The current study examined whether there were differences in baseline grey matter volume (i.e. at initial identification as UHR) in UHR-NT individuals whom had APS compared to those without APS (No-APS) at medium to long-term follow-up. Participants were help-seeking individuals who were identified as being at UHR for psychosis between 2 and 12years previously (mean=7.5). The sample consisted of 109 participants who underwent a Magnetic Resonance Imaging scan at baseline and who had not been observed to develop a psychotic disorder over the follow-up period (UHR-NT). Using voxel-based morphometry, baseline grey matter volume (GMV) was compared between participants with (N=30) and without (N=79) APS at follow-up. At baseline, the APS and No-APS groups were clinically indistinguishable. At follow-up, the APS group had significantly worse symptoms and impaired functioning. Individuals with APS had reduced baseline GMV in frontal, temporal, posterior and cingulate regions compared to those without APS at follow-up. Reduced GMV was associated with more severe positive, negative and depressive symptoms and lower global functioning in the combined UHR-NT cohort. These associations were independent of later APS outcome. This study found that differences in regional GMV are discernible at an early stage of UHR and may be specific to individuals who have APS and psychopathology at follow-up. Our findings suggest that lower GMV at baseline may confer neurobiological risk for later APS and/or increased psychopathology while the absence of these structural abnormalities might be protective. Copyright © 2015 Elsevier B.V. All rights reserved.

Analogs of diadenosine tetraphosphate (Ap4A).

PubMed

Guranowski, Andrzej

2003-01-01

This review summarizes our knowledge of analogs and derivatives of diadenosine 5',5"'-P1,P4-tetraphosphate (Ap4A), the most extensively studied member of the dinucleoside 5',5"'-P1,Pn-polyphosphate (NpnN) family. After a short discussion of enzymes that may be responsible for the accumulation and degradation of Np4)N's in the cell, this review focuses on chemically and/or enzymatically produced analogs and their practical applications. Particular attention is paid to compounds that have aided the study of enzymes involved in the metabolism of Ap4A (Np4N'). Certain Ap4A analogs were alternative substrates of Ap4A-degrading enzymes and/or acted as enzyme inhibitors, some other helped to establish enzyme mechanisms, increased the sensitivity of certain enzyme assays or produced stable enzyme:ligand complexes for structural analysis.

NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability

DOE PAGES

Parplys, Ann C.; Zhao, Weixing; Sharma, Neelam; ...

2015-08-31

NUCKS1 (nuclear casein kinase and cyclin-dependent kinase substrate 1) is a 27 kD chromosomal, vertebrate-specific protein, for which limited functional data exist. Here, we demonstrate that NUCKS1 shares extensive sequence homology with RAD51AP1 (RAD51 associated protein 1), suggesting that these two proteins are paralogs. Similar to the phenotypic effects of RAD51AP1 knockdown, we find that depletion of NUCKS1 in human cells impairs DNA repair by homologous recombination (HR) and chromosome stability. Depletion of NUCKS1 also results in greatly increased cellular sensitivity to mitomycin C (MMC), and in increased levels of spontaneous and MMC-induced chromatid breaks. NUCKS1 is critical to maintainingmore » wild type HR capacity, and, as observed for a number of proteins involved in the HR pathway, functional loss of NUCKS1 leads to a slow down in DNA replication fork progression with a concomitant increase in the utilization of new replication origins. Interestingly, recombinant NUCKS1 shares the same DNA binding preference as RAD51AP1, but binds to DNA with reduced affinity when compared to RAD51AP1. Finally, our results show that NUCKS1 is a chromatin-associated protein with a role in the DNA damage response and in HR, a DNA repair pathway critical for tumor suppression.« less

Dengue virus induces increased activity of the complement alternative pathway in infected cells.

PubMed

Cabezas, Sheila; Bracho, Gustavo; L Aloia, Amanda; Adamson, Penelope J; Bonder, Claudine S; Smith, Justine R; Gordon, David L; Carr, Jillian M

2018-05-09

Severe dengue virus (DENV) infection is associated with overactivity of the complement alternative pathway (AP) in patient studies. Here, the molecular changes in components of the AP during DENV infection in vitro are investigated. mRNA for factor H (FH) a major negative regulator of the AP, is significantly increased in DENV-infected endothelial cells (EC) and macrophages but in contrast production of extracellular FH protein is not. This discord is not seen for the AP activator, factor B (FB), with DENV induction of both FB mRNA and protein, nor with Toll-like receptor 3 or 4 stimulation of EC and macrophages, which induces both FH and FB mRNA and protein. Surface bound and intracellular FH protein is however induced by DENV, but only in DENV antigen-positive cells, while in two other DENV-susceptible immortalised cell lines (ARPE-19 and HREC) FH protein is induced both intracellularly and extracellularly by DENV infection. Regardless of the cell type, there is an imbalance in AP components and an increase in markers of complement AP activity associated with DENV-infected cells - with lower FH relative to FB protein, increased ability to promote AP-mediated lytic activity and increased deposition of complement component C3b on the surface of DENV-infected cells. For EC in particular, these changes are predicted to result in higher complement activity in the local cellular microenvironment, with the potential to induce functional changes that may result in increased vascular permeability, a hallmark of dengue disease. IMPORTANCE Dengue virus (DENV) is a significant human viral pathogen with global medical and economic impact. DENV may cause serious and life-threatening disease with increased vascular permeability and plasma leakage. The pathogenic mechanisms underlying these features remain unclear; however overactivity of the complement alternative pathway has been suggested to play a role. In this study we investigate the molecular events that may be responsible for this observed alternative pathway overactivity and provide novel findings of changes in the complement system in response to DENV infection in primary cell types that are a major target for DENV infection (macrophages) and pathogenesis (endothelial cells) in vivo Our results suggest a new dimension of cellular events that may influence endothelial cell barrier function during DENV infection that could expand strategies for developing therapeutics to prevent or control DENV-mediated vascular disease. Copyright © 2018 American Society for Microbiology.

Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation

PubMed Central

Tohyama, Takeshi; Kawada, Toru; Kishi, Takuya; Yoshida, Keimei; Nishikawa, Takuya; Mannoji, Hiroshi; Kamada, Kazuhiro; Sunagawa, Kenji; Tsutsui, Hiroyuki

2018-01-01

Background Lipopolysaccharide (LPS) induces acute inflammation, activates sympathetic nerve activity (SNA) and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP), examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis. Methods Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg). We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP) by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection. Results In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.). In contrast, AP increased initially (until 75 min), then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship) upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship) downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP. Conclusions LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the augmented neural arc and suppressed peripheral arc determines SNA and hemodynamics in LPS-induced acute inflammation. PMID:29329321

Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation.

PubMed

Tohyama, Takeshi; Saku, Keita; Kawada, Toru; Kishi, Takuya; Yoshida, Keimei; Nishikawa, Takuya; Mannoji, Hiroshi; Kamada, Kazuhiro; Sunagawa, Kenji; Tsutsui, Hiroyuki

2018-01-01

Lipopolysaccharide (LPS) induces acute inflammation, activates sympathetic nerve activity (SNA) and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP), examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis. Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg). We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP) by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection. In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.). In contrast, AP increased initially (until 75 min), then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship) upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship) downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP. LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the augmented neural arc and suppressed peripheral arc determines SNA and hemodynamics in LPS-induced acute inflammation.

Implication of the ERK/MAPK pathway in antipsychotics-induced dopamine D2 receptor upregulation and in the preventive effects of (±)-α-lipoic acid in SH-SY5Y neuroblastoma cells.

PubMed

Deslauriers, Jessica; Desmarais, Christian; Sarret, Philippe; Grignon, Sylvain

2014-03-01

Chronic administration of antipsychotics (APs) has been associated with dopamine D2 receptor (D2R) upregulation and tardive dyskinesia. We previously showed that haloperidol, a first-generation AP, exerted a more robust increase in D2R expression than amisulpride, a second-generation AP and that (±)-α-lipoic acid pre-treatment reversed the AP-induced D2R upregulation. We also demonstrated that the Akt/GSK-3β/β-catenin pathway is involved in the control of D2R expression levels, but is unlikely implicated in the preventive effects of (±)-α-lipoic acid since co-treatment with haloperidol and (±)-α-lipoic acid exerts synergistic effects on Akt/GSK-3β activation. These findings led us to examine whether the ERK/MAPK signaling pathway may be involved in D2R upregulation elicited by APs, and in its reversal by (±)-α-lipoic acid, in SH-SY5Y human neuroblastoma cells. Our results revealed that haloperidol, in parallel with an elevation in D2R mRNA levels, induced a larger increase of ERK (p42/p44) phosphorylation than amisulpride. Pre-treatment with the selective ERK inhibitor U0126 attenuated haloperidol-induced increase in D2R upregulation. Furthermore, (±)-α-lipoic acid prevented AP-induced ERK activation. These results show that (1) the ERK/MAPK pathway is involved in haloperidol-induced D2R upregulation; (2) the preventive effect of (±)-α-lipoic acid on haloperidol-induced D2R upregulation is in part mediated by an ERK/MAPK-dependent signaling cascade. Taken together, our data suggest that (±)-α-lipoic acid exerts synergistic effects with haloperidol on the Akt/GSK-3β pathway, potentially involved in the therapeutic effects of APs, and antagonism of ERK activation and D2R upregulation, potentially involved in tardive dyskinesia and treatment resistance.

Automated cell tracking identifies mechanically oriented cell divisions during Drosophila axis elongation.

PubMed

Wang, Michael F Z; Hunter, Miranda V; Wang, Gang; McFaul, Christopher; Yip, Christopher M; Fernandez-Gonzalez, Rodrigo

2017-04-01

Embryos extend their anterior-posterior (AP) axis in a conserved process known as axis elongation. Drosophila axis elongation occurs in an epithelial monolayer, the germband, and is driven by cell intercalation, cell shape changes, and oriented cell divisions at the posterior germband. Anterior germband cells also divide during axis elongation. We developed image analysis and pattern-recognition methods to track dividing cells from confocal microscopy movies in a generally applicable approach. Mesectoderm cells, forming the ventral midline, divided parallel to the AP axis, while lateral cells displayed a uniform distribution of division orientations. Mesectoderm cells did not intercalate and sustained increased AP strain before cell division. After division, mesectoderm cell density increased along the AP axis, thus relieving strain. We used laser ablation to isolate mesectoderm cells from the influence of other tissues. Uncoupling the mesectoderm from intercalating cells did not affect cell division orientation. Conversely, separating the mesectoderm from the anterior and posterior poles of the embryo resulted in uniformly oriented divisions. Our data suggest that mesectoderm cells align their division angle to reduce strain caused by mechanical forces along the AP axis of the embryo. © 2017. Published by The Company of Biologists Ltd.

Actions of arginine polyamine on voltage and ligand-activated whole cell currents recorded from cultured neurones.

PubMed Central

Scott, R. H.; Sweeney, M. I.; Kobrinsky, E. M.; Pearson, H. A.; Timms, G. H.; Pullar, I. A.; Wedley, S.; Dolphin, A. C.

1992-01-01

1. Toxins from invertebrates have proved useful tools for investigation of the properties of ion channels. In this study we describe the actions of arginine polyamine which is believed to be a close analogue of FTX, a polyamine isolated from the American funnel web spider, Agelenopsis aperta. 2. Voltage-activated Ca2+ currents and Ca(2+)-dependent Cl- currents recorded from rat cultured dorsal root ganglion neurones were reversibly inhibited by arginine polyamine (AP; 0.001 to 100 microM). Low voltage-activated T-type Ca2+ currents were significantly more sensitive to AP than high voltage-activated Ca2+ currents. The IC50 values for the actions of AP on low and high voltage-activated Ca2+ currents were 10 nM and 3 microM respectively. AP was equally effective in inhibiting high voltage-activated currents carried by Ba2+, Sr2+ or Ca2+. However, AP-induced inhibition of Ca2+ currents was attenuated by increasing the extracellular Ca2+ concentration from 2 mM to 10 mM. 3. The actions of AP on a Ca(2+)-independent K+ current were more complex, 1 microM AP enhanced this current but 10 microM AP had a dual action, initially enhancing but then inhibiting the K+ current. 4. gamma-Aminobutyric acid-activated Cl- currents were also reversibly inhibited by 1 to 10 microM AP. In contrast N-methyl-D-aspartate currents recorded from rat cultured cerebellar neurones were greatly enhanced by 10 microM AP. 5. We conclude that at a concentration of 10 nM, AP is a selective inhibitor of low threshold T-type voltage-activated Ca2+ currents.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1380382

Isolation and characterization of the Jatropha curcas APETALA1 (JcAP1) promoter conferring preferential expression in inflorescence buds.

PubMed

Tao, Yan-Bin; He, Liang-Liang; Niu, Longjian; Xu, Zeng-Fu

2016-08-01

The 1.5 kb JcAP1 promoter from the biofuel plant Jatropha curcas is predominantly active in the inflorescence buds of transgenic plants, in which the -1313/-1057 region is essential for maintaining the activity. Arabidopsis thaliana APETALA1 (AP1) is a MADS-domain transcription factor gene that functions primarily in flower development. We isolated a homolog of AP1 from Jatropha curcas (designated JcAP1), which was shown to exhibit flower-specific expression in Jatropha. JcAP1 is first expressed in inflorescence buds and continues to be primarily expressed in the sepals. We isolated a 1.5 kb JcAP1 promoter and evaluated its activity in transgenic Arabidopsis and Jatropha using the β-glucuronidase (GUS) reporter gene. In transgenic Arabidopsis and Jatropha, the inflorescence buds exhibited notable GUS activity, whereas the sepals did not. Against expectations, the JcAP1 promoter was active in the anthers of Arabidopsis and Jatropha and was highly expressed in Jatropha seeds. An analysis of promoter deletions in transgenic Arabidopsis revealed that deletion of the -1313/-1057 region resulted in loss of JcAP1 promoter activity in the inflorescence buds and increased activity in the anthers. These results suggested that some regulatory sequences in the -1313/-1057 region are essential for maintaining promoter activity in inflorescence buds and can partly suppress activity in the anthers. Based on these findings, we hypothesized that other elements located upstream of the 1.5 kb JcAP1 promoter may be required for flower-specific activation. The JcAP1 promoter characterized in this study can be used to drive transgene expression in both the inflorescence buds and seeds of Jatropha.

Antibiotic prophylaxis audit and questionnaire study: Traffic Light Poster improves adherence to protocol in gastrointestinal surgery.

PubMed

Cameron, Michaella; Jones, Stacey; Adedeji, Olufunso

2015-07-01

To measure adherence to antibiotic prophylaxis (AP) protocol amongst surgeons and anesthetists and explore their understanding of AP prescribing in practice. A prospective audit of AP in gastrointestinal surgery and re-audit after intervention. A questionnaire survey of practice. 58 (38%- clean; 62%- clean contaminated) operations were audited and 73 (48%-clean; 51%-clean contaminated) operations were re-audited after intervention with "Traffic Light Poster" (TFP) .55 colleagues (32 consultants and 23 trainees) were recruited for questionnaire survey in three West Midlands hospitals. Audit and Re-Audits. Only 31% of procedures followed the protocol correctly in the initial audit and this increased to 73% in the re-audit. 73% of patients undergoing clean procedures received AP inappropriately in the initial audit but reduced significantly to 20% (p < 0.002) in the re-audit. In the initial audit, 62% of clean contaminated procedures did not receive the appropriate first line AP but this fell to 35% (p < 0.05) in the re-audit. Questionnaire Survey- Only 30% of respondents would not give AP in clean surgery as recommended. 45% would use appropriate AP for clean-contaminated wounds. 73% of respondents will give AP at induction, 20% 1 h pre op and 7% just before incision. There is poor compliance with AP protocols in gastrointestinal surgery in part due to general lack of awareness. An educational intervention in the form of a 'Traffic Light Poster' improved adherence to AP protocol two fold. There was improved rationalizing of AP. Clean procedures, in particular, had less inappropriate prescribing. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

Clinical application of diadenosine tetraphosphate (Ap4A:F-1500) for controlled hypotension.

PubMed

Kikuta, Y; Ohiwa, E; Okada, K; Watanabe, A; Haruki, S

1999-01-01

In our animal study, it was revealed that diadenosine tetraphosphate (Ap4A:F-1500) has a dose-dependent hypotension effect of up to 60% decrease in mean arterial pressure compared to control value. Furthermore, in healthy male volunteers, the safety of Ap4A up to 4 mg.min-1 was confirmed. In patients who require surgical procedures under general anesthesia together with controlled hypotension, hypotension was induced by Ap4A in order to examine its hypotensive effect and modulating action on the blood pressure. Ten patients who required controlled hypotension and who were scheduled for elective surgery under general anesthesia were studied. Anesthesia was maintained with isoflurane (n = 7) or sevoflurane (n = 3) in oxygen-nitrous oxide. Controlled hypotension was induced by Ap4A administered at a rate of 10-20 micrograms.kg-1.min-1. The dose was adjusted at a maximum rate of 80 micrograms.kg-1.min-1 until the target blood pressure was achieved. Arterial blood pressure and heart rate were monitored. Arterial samples were drawn at 4 separate time points to measure the concentration of Ap4A in the plasma. The time required for attaining the target blood pressure after initiation of Ap4A infusion was about 16 min, and the time lapse between withdrawal of infusion to recovery of blood pressure was about 18 min. No reflex tachycardia was observed during infusion of Ap4A and no rebound hypertension was evident after withdrawal. The plasma Ap4A concentration increased in response to the acceleration rate of Ap4A administration with a tendency of augmented hypotensive effect. As it produces an excellent hypotensive effect together with a modulating action on blood pressure, Ap4A was assessed as useful in producing controlled hypotension.

Omega 3 Fatty Acids Reduce Bone Resorption While Promoting Bone Generation in Rat Apical Periodontitis.

PubMed

Azuma, Mariane Maffei; Gomes-Filho, João Eduardo; Ervolino, Edilson; Pipa, Camila Barbosa; Cardoso, Carolina de Barros Morais; Andrada, Ana Cristina; Kawai, Toshihisa; Cintra, Luciano Tavares Angelo

2017-06-01

This study evaluated the effects of the dietary supplement omega 3 polyunsaturated fatty acids (ω-3 PUFAs) on pulp exposure-induced apical periodontitis (AP) in rats. Twenty-eight male rats were divided into groups: control untreated rats (C), control rats treated with ω-3 PUFAs alone (C-O), rats with pulp exposure-induced AP, and rats with pulp exposure-induced AP treated with ω-3 PUFAs (AP-O). The ω-3 PUFAs were administered orally, once a day, for 15 days before pulp exposure and, subsequently, 30 days after pulp exposure. Rats were killed 30 days after pulp exposure, and jaws were subjected to histologic and immunohistochemical analyses. Immunohistochemical analyses were performed to detect tartrate-resistant acid phosphatase-positive osteoclasts and osteocalcin-positive osteoblasts on the bone surface of periapical area. Results were statistically evaluated by using analysis of variance and Tukey honestly significant difference, and P < .05 was considered statistically significant. The bone resorption lesion was significantly larger in the AP group compared with AP-O, C, and C-O groups (P < .05). The level of inflammatory cell infiltration was significantly elevated, and the number of tartrate-resistant acid phosphatase-positive osteoclasts was significantly higher in the periapical lesions of the AP group compared with AP-O, C, and C-O groups (P < .05). The number of osteocalcin-positive osteoblasts was significantly increased in the AP-O group compared with the AP group (P > .05). Supplementation with ω-3 PUFAs not only suppresses bone resorption but also promotes new bone formation in the periapical area of rats with AP in conjunction with downregulation of inflammatory cell infiltration into the lesion. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Angelica polysaccharides inhibit the growth and promote the apoptosis of U251 glioma cells in vitro and in vivo.

PubMed

Zhang, Wen-Feng; Yang, Yan; Li, Xin; Xu, Da-Yan; Yan, Yu-Li; Gao, Qiao; Jia, Ai-Ling; Duan, Ming-Hua

2017-09-15

Angelica sinensis (Oliv) Diels (Apiaceae) is a traditional medicine that has been used for more than 2000 years in China. It exhibits various therapeutic effects including neuroprotective, anti-oxidant, anti-inflammatory, and immunomodulatory activities. Angelica polysaccharides (APs), bioactive constituents of Angelica have been shown to be responsible for these effects; however, the utility of APs for the treatment of glioma and their mechanism of action remain to be elucidated. In this study, we investigated the inhibitory effects of APs on a glioma cell line and their molecular mechanism of action. U251 cells were utilized to confirm the effects of APs on glioma. The human glioblastoma cell line U251 was utilized for both in vitro and in vivo models, in which we tested the effects of APs. Flow cytometry, gene expression analysis, western blotting, and MTT assays were used to elucidate the effects of APs on cell proliferation, cell cycle, and apoptosis. The results demonstrated that APs significantly inhibited the growth and proliferation of U251 cells and induced their apoptosis. Furthermore, APs effectively reduced the expression of several cell cycle regulators: cyclins D1, B, and E. The apoptosis suppressor protein Bcl-2 was also downregulated, and the expression of pro-apoptotic proteins Bax and cleaved-caspase-3 increased. Additionally, APs inhibited the transforming growth factor (TGF)-β signaling pathway and stimulated the expression of E-cadherin, thus prohibiting cell growth. In conclusion, the results indicate that APs attenuate the tumorigenicity of glioma cells and promote their apoptosis by suppressing the TGF-β signaling pathway. The present study therefore provides evidence of the inhibitory effects of APs against glioma progression, and proposes their potential application as alternative therapeutic agents for glioma. Copyright © 2017 Elsevier GmbH. All rights reserved.

Type III Radio Burst Duration and SEP Events

NASA Technical Reports Server (NTRS)

Gopalswamy, N.; Makela, P.; Xie, H.

2010-01-01

Long-duration (>15 min), low-frequency (<14 MHz) type III radio bursts have been reported to be indicative of solar energetic particle events. We measured the durations of type III bursts associated with large SEP events of solar cycle 23. The Type III durations are distributed symmetrically at 1 MHz yielding a mean value of approximately 33 min (median = 32 min) for the large SEP events. When the SEP events with ground level enhancement (GLE,) are considered, the distribution is essentially unchanged (mean = 32 min, median = 30 min). To test the importance of type III bursts in indicating SEP events, we considered a set of six type III bursts from the same active region (AR 10588) whose durations fit the "long duration" criterion. We analyzed the coronal mass ejections (CMEs), flares, and type II radio bursts associated with the type III bursts. The CMEs were of similar speeds and the flares are also of similar size and duration. All but one of the type III bursts was not associated with a type II burst in the metric or longer wavelength domains. The burst without type II burst also lacked a solar energetic particle (SEP) event at energies >25 MeV. The 1-MHz duration of the type III burst (28 rein) is near the median value of type III durations found for gradual SEP events and ground level enhancement (GLE) events. Yet, there was no sign of SEP events. On the other hand, two other type III bursts from the same active region had similar duration but accompanied by WAVES type 11 bursts; these bursts were also accompanied by SEP events detected by SOHO/ERNE. This study suggests that the type III burst duration may not be a good indicator of an SEP event, consistent with the statistical study of Cliver and Ling (2009, ApJ ).

Application of solid state NMR for the study of surface bound species and fossil fuels

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

Althaus, Stacey

2014-01-01

In this study, stimulated echo with pulsed field gradients was used to measure the diffusion of two different solvents, water and hexane, in AP-MSN-2.7 and AP-MSN-3.7. The resulting data were then fit using two different methods. Based on these fits, the diffusion of hexane in AP-MSN-2.7 was shown to be slower than in the larger pores. This agrees well with our studies of catalytic activity, which show an increase in the reaction rate with the increase in pore size. Thus, both substrate inhibition and diffusion played a role in the decreased efficiency of the APMSN with small pore sizes.

Canine Pancreas-Specific Lipase and C-reactive Protein in Dogs Treated With Anticonvulsants (Phenobarbital and Potassium Bromide).

PubMed

Albarracín, Viviana; Teles, Mariana; Meléndez-Lazo, Antonio; Rodón, Jaume; Pastor, Josep

2015-06-01

Animals treated with anticonvulsant drugs may have increased canine pancreas-specific lipase (cPLI) values. Inflammatory conditions and specifically acute pancreatitis are of major concern in these animals. Elevation in C-reactive protein is being associated with inflammatory status in dogs and it has been correlated with the clinical severity of pancreatitis. In the present study, we investigated if there is a correlation between the cPLI increase, changes in C-reactive protein and hepatic enzymes, as well as the incidence of severe acute pancreatitis (AP) in dogs with anticonvulsant treatment (phenobarbital, or potassium bromide or both). Increased values of pancreas-specific lipase were found in 6.8% of the animals in treatment with anticonvulsants, and this increase is correlated with the increase in triglycerides, alkaline phosphatase, and alanine aminotransferase but not with C-reactive protein levels, which suggests a possible induction or release phenomenon rather than a clear severe AP. C-reactive protein levels did not affect cPLI values on the population studied. Only 2 animals had clinical and analytical data suggestive of AP, indicating a low prevalence (0.6%). In conclusion, cPLI may be increased in a low percentage of animals with anticonvulsants treatment and its increase may not be associated with severe AP. It may be induced by the anticonvulsants drugs; however, further studies are advised to rule out other possible causes that increased cPLI. Copyright © 2015 Elsevier Inc. All rights reserved.

Collisional Quenching of No A2sigma+(nu’= 0) Between 125 and 294 (Postprint)

DTIC Science & Technology

2009-05-28

using an oil-free pumping system consisting of a turbomolecular pump backed by a dry scroll pump . The measured leak rate of the cell was less than 10...mode-locked laser producing pulses of approximately 100 ps duration, was used to pump a DFDL, a side- pumped dye amplifier, and an end- pumped dye...conditions, the calibrated pressure Vacuum C N2 Laser PMTMono L2 L3 Cryostat W1 W2 L1 L1 Ap ND FIG. 1. Experimental arrangement with section detail of cryostat

Antioxidant Effect of Ukrain Versus N-Acetylcysteine Against Acute Biliary Pancreatitis in An Experimental Rat Model.

PubMed

Zeren, Sezgin; Bayhan, Zulfu; Koçak, Cengiz; Koçak, Fatma Emel; Metineren, Mehmet Huseyin; Savran, Bircan; Kocak, Havva; Algin, Mustafa Cem; Kahraman, Cuneyt; Kocak, Ahmet; Cosgun, Suleyman

2017-04-01

Purpose/Aim: Oxidative stress plays an important role in the pathogenesis of acute pancreatitis (AP). We compared the therapeutic effects of Ukrain (NSC 631570) and N-acetylcysteine (NAC) in rats with AP. Forty male Sprague Dawley rats were divided into four groups: controls; AP; AP with NAC; and AP with Ukrain. AP was induced via the ligation of the bile-pancreatic duct; drugs were administered intraperitoneally (i.p.) 30 min and 12 h after AP induction. Twenty-four hours after AP induction, animals were sacrificed and the pancreas was excised. Levels of malondialdehyde (MDA) and nitric oxide (NO), and activity levels of tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO) were measured in tissue samples. Total oxidant status (TOS), total antioxidant status (TAS), and total bilirubin, as well as activity levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase and lipase were measured in serum samples. Pancreatic tissue histopathology was also evaluated. Test drugs reduced levels of MDA, NO, TNF-α, total bilirubin, AST, ALT, TOS and MPO, amylase and lipase activities (P < 0.001), and increased TAS (P < 0.001). Rats treated with test drugs attenuated AP-induced morphologic changes and decreased pancreatic damage scores compared with the AP group (P < 0.05). Both test drugs attenuated pancreatic damage, but the therapeutic effect was more pronounced in rats that received Ukrain than in those receiving NAC. These results suggest that treatment with Ukrain or NAC can reduce pancreatic damage via anti-inflammatory and antioxidant effects.

Some properties of the action potentials conducted in the spines of the sea urchin Diadema antillarum.

PubMed

Berrios, A; Brink, D; del Castillo, J; Smith, D S

1985-01-01

Brief (2-5 msec) electrical pulses applied to the primary spines of the sea urchin Diadema antillarum elicit graded action potentials (ap's). These ap's can be attributed to the electrical activity of a set of 14-21 bundles of neurites, each comprising 1000 processes near the spine base and tapering towards the spine tip. The shape of the ap's varies from a simple diphasic deflection to a complex waveform with 6 or more components. Peak-to-peak amplitude is less than 1mV. The ap's are conducted at a uniform speed of ca. 27 cm/sec. The ap's are not affected by tetrodotoxin (1 microgram/ml) and continue to be produced in Na-free artificial sea water (ASW). The amplitude of the ap's is greatly reduced or totally abolished in Ca-free ASW. However, some electrical activity may continue in the absence of external Ca, due to release of Ca2+ ions from the calcium carbonate crystals of the spine shaft. Replacing the Ca content of ASW by barium ions causes an irreversible blockade of the ap's. Spines equilibrated with ASW containing Sr2+ ions instead of Ca2+ produce ap's of increased amplitude (up to X 2). The ap's are blocked by La3+, Co2+, Cd2+ (2-5 mM) and by the organic Ca channel blocker Bepridil (2 mM). We conclude that the spinal ap's are due to the summation of Ca spikes produced by the activation of Ca channels which are blocked by barium and have a high affinity for, or permeability to Sr vs Ca.

Cardiotoxicity screening with simultaneous optogenetic pacing, voltage imaging and calcium imaging.

PubMed

Dempsey, Graham T; Chaudhary, Khuram W; Atwater, Nicholas; Nguyen, Cuong; Brown, Barry S; McNeish, John D; Cohen, Adam E; Kralj, Joel M

2016-01-01

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative seeks an in vitro test to accurately predict clinical Torsades de Pointes (TdP). We developed a cardiotoxicity assay incorporating simultaneous measurement of the action potential (AP) waveform and Ca(2+) transient (CT) in human iPSC-derived cardiomyocytes (CMs). Concurrent optogenetic pacing provided a well-controlled electrophysiological background. We used the Optopatch platform for all-optical electrophysiology (Hochbaum et al., 2014). In a monolayer culture, a subset of cells expressed a genetically encoded, calcium and voltage reporter, CaViar (Hou, Kralj, Douglass, Engert, & Cohen, 2014), while others expressed a channelrhodopsin variant, CheRiff. Optical pacing of CheRiff-expressing cells synchronized the syncytium. We screened 12 compounds (11 acute, 1 chronic) to identify electrophysiological (AP rise time, AP50, AP90, beat rate) and CT effects in spontaneously beating and paced cultures (1Hz, 2Hz). CaViar reported spontaneous and paced APs and CTs with high signal-to-noise ratio and low phototoxicity. Quinidine, flecainide, E-4031, digoxin and cisapride prolonged APs, while verapamil and nifedipine shortened APs. Early after depolarizations (EADs) were elicited by quinidine, flecainide and cisapride. All but four compounds (amiodarone, chromanol, nifedipine, verapamil) prolonged AP rise time. Nifedipine and verapamil decreased CT amplitude, while digoxin increased CT amplitude. Pentamidine prolonged APs after chronic exposure. The Optopatch platform provides a robust assay to measure APs and CTs in hiPSC-CMs. This addresses the CiPA mandate and will facilitate comparisons of cell-based assays to human clinical data. Copyright © 2016 Elsevier Inc. All rights reserved.

Symptoms after ingestion of pig whipworm Trichuris suis eggs in a randomized placebo-controlled double-blind clinical trial.

PubMed

Bager, Peter; Kapel, Christian; Roepstorff, Allan; Thamsborg, Stig; Arnved, John; Rønborg, Steen; Kristensen, Bjarne; Poulsen, Lars K; Wohlfahrt, Jan; Melbye, Mads

2011-01-01

Symptoms after human infection with the helminth Trichuris suis have not previously been described. Exposure to helminths has been suggested as immune therapy against allergy and autoimmune diseases. We randomized adults with allergic rhinitis to ingest a dose of 2500 T. suis eggs or placebo every 21 days for 168 days (total 8 doses) in a double-blind clinical trial. In a previous publication, we reported a lack of efficacy and a high prevalence of adverse gastrointestinal reactions. The aim of the present study was to present a detailed description of the adverse event data and post-hoc analyses of gastrointestinal reactions. Adverse events and severity (mild, moderate, severe) were recorded daily by subjects, classified by organ using MedDRA 10.0, and event rates compared between subjects on T. suis treatment vs. subjects on placebo. T. suis-specific serum IgG antibodies were measured by a fluoroenzymeimmunoassay (Phadia ApS). During 163 days complete follow-up, subjects ingesting T. suis eggs (N = 49) had a three to 19-fold higher rate of events (median duration, 2 days) with gastrointestinal reactions (moderate to severe flatulence, diarrhea, and upper abdominal pain) compared with placebo subjects (N = 47). The highest incidence of affected subjects was seen from the first few days and until day 42 (3(rd) dose): 63% vs. 29% for placebo; day 163: 76% vs. 49% for placebo. Seroprevalences increased concurrently in the T. suis group: Day 59, 50%; day 90, 91%; day 170, 93%. The combined duration of episodes with onset before day 42 was ≤ 14 days in 80% of affected subjects. Age, gender, total IgE, and recent intestinal symptoms at baseline did not predict gastrointestinal side effects. In conclusion, during the first 2 months, repeated ingestions of 2500 T. suis eggs caused frequent gastrointestinal reactions lasting up to 14 days, whereas 4 months further treatment mainly provoked a subclinical stimulation. University hospital Medical Information Network trial registry Reg. no. R000001298, Trial ID UMIN000001070.

Symptoms after Ingestion of Pig Whipworm Trichuris suis Eggs in a Randomized Placebo-Controlled Double-Blind Clinical Trial

PubMed Central

Bager, Peter; Kapel, Christian; Roepstorff, Allan; Thamsborg, Stig; Arnved, John; Rønborg, Steen; Kristensen, Bjarne; Poulsen, Lars K.; Wohlfahrt, Jan; Melbye, Mads

2011-01-01

Symptoms after human infection with the helminth Trichuris suis have not previously been described. Exposure to helminths has been suggested as immune therapy against allergy and autoimmune diseases. We randomized adults with allergic rhinitis to ingest a dose of 2500 T. suis eggs or placebo every 21 days for 168 days (total 8 doses) in a double-blind clinical trial. In a previous publication, we reported a lack of efficacy and a high prevalence of adverse gastrointestinal reactions. The aim of the present study was to present a detailed description of the adverse event data and post-hoc analyses of gastrointestinal reactions. Adverse events and severity (mild, moderate, severe) were recorded daily by subjects, classified by organ using MedDRA 10.0, and event rates compared between subjects on T. suis treatment vs. subjects on placebo. T. suis-specific serum IgG antibodies were measured by a fluoroenzymeimmunoassay (Phadia ApS). During 163 days complete follow-up, subjects ingesting T. suis eggs (N = 49) had a three to 19-fold higher rate of events (median duration, 2 days) with gastrointestinal reactions (moderate to severe flatulence, diarrhea, and upper abdominal pain) compared with placebo subjects (N = 47). The highest incidence of affected subjects was seen from the first few days and until day 42 (3rd dose): 63% vs. 29% for placebo; day 163: 76% vs. 49% for placebo. Seroprevalences increased concurrently in the T. suis group: Day 59, 50%; day 90, 91%; day 170, 93%. The combined duration of episodes with onset before day 42 was ≤14 days in 80% of affected subjects. Age, gender, total IgE, and recent intestinal symptoms at baseline did not predict gastrointestinal side effects. In conclusion, during the first 2 months, repeated ingestions of 2500 T. suis eggs caused frequent gastrointestinal reactions lasting up to 14 days, whereas 4 months further treatment mainly provoked a subclinical stimulation. Trial registration University hospital Medical Information Network trial registry Reg. no. R000001298, Trial ID UMIN000001070. PMID:21829616

APS Science 2009.

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

Gibson, J. M; Mills, D. M.; Gerig, R.

It is my pleasure to introduce the 2009 annual report of the Advanced Photon Source. This was a very good year for us. We operated with high reliability and availability, despite growing problems with obsolete systems, and our users produced a record output of publications. The number of user experiments increased by 14% from 2008 to more than 3600. We congratulate the recipients of the 2009 Nobel Prize in Chemistry-Venkatraman Ramakrishnan (Cambridge Institute for Medical Research), Thomas Steitz (Yale University), and Ada Yonath (Weizmann Institute) - who did a substantial amount of this work at APS beamlines. Thanks to themore » efforts of our users and staff, and the ongoing counsel of the APS Scientific Advisory Committee, we made major progress in advancing our planning for the upgrade of the APS (APS-U), producing a proposal that was positively reviewed. We hope to get formal approval in 2010 to begin the upgrade. With advocacy from our users and the support of our sponsor, the Office of Basic Energy Sciences in the Department of Energy (DOE) Office of Science, our operating budgets have grown to the level needed to more adequately staff our beamlines. We were also extremely fortunate to have received $7.9 M in American Recovery and Reinvestment Act ('stimulus') funding to acquire new detectors and improve several of our beamlines. The success of the new Linac Coherent Light Source at Stanford, the world's first x-ray free-electron laser, made us particularly proud since the undulators were designed and built by the APS. Among other highlights, we note that more than one-quarter of the 46 Energy Frontier Research Centers, funded competitively across the U.S. in 2009 by the DOE, included the Advanced Photon Source in their proposed work, which shows that synchrotron radiation, and the APS in particular, are central to energy research. While APS research covers everything from fundamental to applied science (reflected by the highlights in this report), the challenge of sustainable energy provides an opportunity for expanded involvement with industrial research. We were privileged to recruit several outstanding new leaders at the APS. Linda Young, from Argonne's Chemical Sciences Division, became the new Director of the X-ray Science Division (XSD). Chris Jacobsen (from Stony Brook University) has been added to Linda's team as an XSD Associate Division Director, joining George Srajer. Alexander (Sasha) Zholents (formerly of Berkeley Lab) became Director of the Accelerator Systems Division. Sasha is the inventor of the short-pulse x-ray scheme that we plan to implement in the APS-U to obtain very high average brightness, broadband, 1-ps x-ray pulses. Walter Lowe (formerly of Howard University) has taken a new position as senior advisor for outreach and development of the user community. Walter's role is to increase the diversity of the user community (with diversity read broadly to include users, institutions, and technical disciplines that are underrepresented at APS). Walter is also leading an effort to increase access for industrial users. I am confident that we have in place a great team to help our users and the APS take fullest advantage of the APS-U opportunity. In planning with users for the proposed APS-U, we focused on the need to study 'real materials under real conditions in real time' on spatial and temporal scales unavailable today. Only by studying materials as they are made-or as they perform-in difficult environments can we solve the grand challenge of higher-performance, sustainable materials for energy and health. The proposed APS-U will improve the brightness of penetrating x-rays produced by the APS over 100 times, and support our efforts in developing state-of-the-art instruments to address these challenges.« less

Transport of IRW, an ovotransferrin-derived antihypertensive peptide, in human intestinal epithelial Caco-2 cells.

PubMed

Bejjani, Satyanarayana; Wu, Jianping

2013-02-20

IRW is an egg ovotransferrin-derived ACE inhibitory peptide. The purpose of this study was to evaluate the stability and transcellular transport of IRW in Caco-2 cell monolayers. The stability of IRW was monitored on the apical (AP) surface while its transport was studied from AP to basal (BL) and from BL to AP surfaces. The results revealed that IRW is resistant against intestinal peptidase up to 60 min. Transport of IRW was not affected by addition of wortamanin, a transcytosis inhibitor. However, in the presence of cytochalasin D, a gap junction disruptor, transport of IRW was significantly increased, suggesting a possible passive transport from AP to BL surface. A higher transport of IRW from AP to BL surface than that from BL to AP surface suggests a passive-mediated transport. Moreover, in the presence of glycyl-sarcosine, a substrate for peptide transporter PepT 1, transport of IRW was reduced from AP to BL surface. The above observations showed atypical transport of IRW in Caco-2 cell monolayers. Thus, IRW may possibly be absorbed intact into the site of action for controlling hypertension.

United States Air Force Summer Research Program -- 1993. Volume 2. Armstrong Laboratory

DTIC Science & Technology

1993-12-01

increase of both left and right hearts as ... Ahl = (h2 - h,) + (h., - h3) (h 2 - h) = cATLH + vAPH (h, - h3) = cAT • + vAP, next applying the 1st law to...CATR T Cs *-hC3 ,C, v P,- jA -HV + vAPc 3 + AG)T a=-HV+ AG)T.P -tuAPc2,c, + cATLH + cATRH + cAT , Since AG)T.P Wrev and Wact = HV - CATC, assuming Q2...Ah3 - vAP, - ,AN, -- HV + cAT , + vAP, + AG)TI mis (- HV +cAT3 + vAPý G), C;=iMs (- HV+ AG +vAP,,),,) PULMONARY CIRCULATION: Shown below is the schematic

Economic considerations and health in all policies initiatives: evidence from interviews with key informants in Sweden, Quebec and South Australia.

PubMed

Pinto, Andrew D; Molnar, Agnes; Shankardass, Ketan; O'Campo, Patricia J; Bayoumi, Ahmed M

2015-02-18

Health in All Policies (HiAP) is a form of intersectoral action that aims to include the promotion of health in government initiatives across sectors. To date, there has been little study of economic considerations within the implementation of HiAP. As part of an ongoing program of research on the implementation of HiAP around the world, we examined how economic considerations influence the implementation of HiAP. By economic considerations we mean the cost and financial gain (or loss) of implementing a HiAP process or structure within government, or the cost and financial gain (or loss) of the policies that emerge from such a HiAP process or structure. We examined three jurisdictions: Sweden, Quebec and South Australia. Semi-structured telephone interviews were conducted with 12 to 14 key informants in each jurisdiction. Two investigators separately coded transcripts to identify relevant statements. Initial readings of transcripts led to the development of a coding framework for statements related to economic considerations. First, economic evaluations of HiAP are viewed as important for prompting HiAP and many forms of economic evaluation were considered. However, economic evaluations were often absent, informal, or incomplete. Second, funding for HiAP initiatives is important, but is less important than a high-level commitment to intersectoral collaboration. Furthermore, having multiple sources of funding of HiAP can be beneficial, if it increases participation across government, but can also be disadvantageous, if it exposes underlying tensions. Third, HiAP can also highlight the challenge of achieving both economic and social objectives. Our results are useful for elaborating propositions for use in realist multiple explanatory case studies. First, we propose that economic considerations are currently used primarily as a method by health sectors to promote and legitimize HiAP to non-health sectors with the goal of securing resources for HiAP. Second, allocating resources and making funding decisions regarding HiAP are inherently political acts that reflect tensions within government sectors. This study contributes important insights into how intersectoral action works, how economic evaluations of HiAP might be structured, and how economic considerations can be used to both promote HiAP and to present barriers to implementation.

Rotational dynamics of coumarin-153 and 4-aminophthalimide in 1-ethyl-3-methylimidazolium alkylsulfate ionic liquids: effect of alkyl chain length on the rotational dynamics.

PubMed

Das, Sudhir Kumar; Sarkar, Moloy

2012-01-12

Rotational dynamics of two neutral organic solutes, coumarin-153 (C-153) and 4-aminophthalimide (AP), with only the latter having hydrogen-bond-donating ability, has been investigated in a series of 1-ethyl-3-methylimidazolium alkyl sulfate ionic liquids as a function of temperature. The ionic liquids differ only in the length of the linear alkyl side chain (alkyl = ethyl, butyl, hexyl, and octyl) on the anionic moiety. The present study has been undertaken to examine the role of alkyl side chains on the rotational dynamics of the two solutes in these ionic liquids. Analysis of the results using Stokes-Einstein-Debye hydrodynamic theory indicates that the rotational dynamics of C-153 lies between the stick and slip boundary condition in the ethyl analogue and finally reaches subslip condition as in case of the octyl substituent. The observed rotational behavior of C-153 has been explained on the basis of an increase in the size of the solvent, which offers lower friction for solute rotation. On the other hand, AP shows superstick behavior in the ethyl system and exceeds the stick limit in the octyl derivative. Superstick behavior of AP has been attributed to the specific hydrogen-bonding interaction between AP and the sulfate moiety. Proton NMR investigation confirms the hydrogen-bonding interaction between the N-H hydrogen of AP and the ionic liquid. The decrease in rotational coupling constant values for AP with increasing length of alkyl side chains has been attributed to the decrease in the solute-solvent-specific interaction with an increase in the alkyl side chain length on the sulfate moiety.

Changes in diadenosine polyphosphates during alignment-fit and orthokeratology rigid gas permeable lens wear.

PubMed

Carracedo, Gonzalo; González-Méijome, José Manuel; Pintor, Jesús

2012-07-03

To evaluate the levels of dinucleotides diadenosine tetraphosphate (Ap(4)A) and diadenosine pentaphosphate (Ap(5)A) in tears of patients wearing rigid gas permeable (RGP) contact lenses on a daily wear basis and of patients wearing reverse-geometry RGP lenses overnight for orthokeratology treatment. Twenty-two young volunteers (10 females, 12 males; 23.47 ± 4.49 years) were fitted with an alignment-fit RGP lens (paflufocon B) for a month, and after a 15-day washout period they were fitted with reverse-geometry RGP lenses for corneal reshaping (paflufocon D) for another month. During each period, tears were collected at baseline day 1, 7, 15, and 28. Ap(4)A and Ap(5)A were measured by high-pressure liquid chromatography (HPLC). Additionally, corneal staining, break-up time (BUT), Schirmer test, and dryness symptoms were evaluated. Ap(4)A concentrations increased significantly from baseline during the whole period of daily wear of RGP lenses (P < 0.001); concentration was also significantly higher than in the orthokeratology group, which remained at baseline levels during the study period except at day 1 (P < 0.001) and day 28 (P = 0.041). While BUT and Schirmer remained unchanged in both groups, discomfort and dryness were significantly increased during alignment-fit RGP daily wear but not during the orthokeratology period. Daily wear of RGP lenses increased the levels of Ap(4)A due to mechanical stimulation by blinking of the corneal epithelium, and this is associated with discomfort. Also, orthokeratology did not produce symptoms or signs of ocular dryness, which could be a potential advantage over soft contact lenses in terms of contact lens-induced dryness.

Diadenosine tetraphosphate induces tight junction disassembly thus increasing corneal epithelial permeability.

PubMed

Loma, P; Guzman-Aranguez, A; Pérez de Lara, M J; Pintor, J

2015-02-01

Here, we have studied the effects of the dinucleotide P(1), P(4)-Di (adenosine-5') tetraphosphate (Ap4 A) on corneal barrier function conferred by the tight junction (TJ) proteins and its possible involvement in ocular drug delivery and therapeutic efficiency. Experiments in vitro were performed using human corneal epithelial cells (HCLEs) treated with Ap4 A (100 μM) for 5 min. Western blot analysis and transepithelial electrical resistance (TEER) were performed to study the TJ protein levels and barrier function respectively. Intracellular pathways involved were determined using an ERK inhibitor and P2Y(2) receptor siRNAs. In in vivo assays with New Zealand rabbits, TJ integrity was examined by zonula occludens-1 (ZO-1) staining. The hypotensive compound 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) was used to assess improved delivery, measuring its levels by HPLC and measuring intraocular pressure using 5-MCA-NAT, P2Y receptor antagonists and P2Y2 siRNAs. Two hours after Ap4 A pretreatment, TJ protein levels in HCLE cells were reduced around 40% compared with control. TEER values were significantly reduced at 2 and 4 h (68 and 52% respectively). TJ reduction and ERK activation were blocked by the ERK inhibitor U012 and P2Y(2) siRNAs. In vivo, topical application of Ap4 A disrupted ZO-1 membrane distribution. 5-MCA-NAT levels in the aqueous humour were higher when Ap4 A was previously instilled and its hypotensive effect was also increased. This action was reversed by P2Y receptor antagonists and P2Y(2) siRNA. Ap4 A increased corneal epithelial barrier permeability. Its application could improve ocular drug delivery and consequently therapeutic efficiency. © 2014 The British Pharmacological Society.

Artificial reproduction of magnetic fields produced by a natural geomagnetic storm increases systolic blood pressure in rats.

PubMed

Martínez-Bretón, J L; Mendoza, B; Miranda-Anaya, M; Durán, P; Flores-Chávez, P L

2016-11-01

The incidence of geomagnetic storms may be associated with changes in circulatory physiology. The way in which the natural variations of the geomagnetic field due to solar activity affects the blood pressure are poorly understood and require further study in controlled experimental designs in animal models. In the present study, we tested whether the systolic arterial pressure (AP) in adult rats is affected by simulated magnetic fields resembling the natural changes of a geomagnetic storm. We exposed adult rats to a linear magnetic profile that simulates the average changes associated to some well-known geomagnetic storm phases: the sudden commencement and principal phase. Magnetic stimulus was provided by a coil inductor and regulated by a microcontroller. The experiments were conducted in the electromagnetically isolated environment of a semi-anechoic chamber. After exposure, AP was determined with a non-invasive method through the pulse on the rat's tail. Animals were used as their own control. Our results indicate that there was no statistically significant effect in AP when the artificial profile was applied, neither in the sudden commencement nor in the principal phases. However, during the experimental period, a natural geomagnetic storm occurred, and we did observe statistically significant AP increase during the sudden commencement phase. Furthermore, when this storm phase was artificially replicated with a non-linear profile, we noticed a 7 to 9 % increase of the rats' AP in relation to a reference value. We suggested that the changes in the geomagnetic field associated with a geomagnetic storm in its first day could produce a measurable and reproducible physiological response in AP.

Hypoglycaemia, chronic kidney disease and death in type 2 diabetes: the Hong Kong diabetes registry

PubMed Central

2014-01-01

Background In patients with type 2 diabetes, chronic kidney disease (CKD) is associated with increased risk of hypoglycaemia and death. Yet, it remains uncertain whether hypoglycaemia-associated mortality is modified by CKD. Methods Type 2 diabetic patients, with or without CKD at enrolment were observed between 1995 and 2007, and followed up till 2009 at hospital medical clinics. We used additive interaction, estimated by relative excess risk due to interaction (RERI) and attributable proportion due to interaction (AP) to examine possible synergistic effects between CKD and severe hypoglycaemia (defined as hospitalisations due to hypoglycaemia in the 12 months prior to enrolment) on the risk of death. Results In this cohort of 8,767 type 2 diabetic patients [median age: 58 (interquartile range: 48 to 68) years; disease duration: 5 (1 to 11) years, men: 47.0%], 1,070 (12.2%) had died during a median follow-up period of 6.66 years (3.42-10.36) with 60,379 person-years.Upon enrolment, 209 patients had severe hypoglycaemia and 194 developed severe hypoglycaemia during follow-up (15 patients had both). In multivariable analysis and using patients without severe hypoglycaemia nor CKD as the referent group (683 deaths in 7,598 patients), severe hypoglycaemia alone (61 deaths in 272 patients) or CKD alone (267 death in 781 patients) were associated with increased risk of death [Hazard ratio, HR: 1.81(95%CI: 1.38 to 2.37) and 1.63 (1.38 to 1.93) respectively]. Having both risk factors (59 deaths in 116 patients) greatly enhanced the HR of death to 3.91 (2.93 to 5.21) with significant interaction (RERI: 1.46 and AP: 0.37, both p-values < 0.05). Conclusions Severe hypoglycaemia and CKD interact to increase risk of death in type 2 diabetes patients. PMID:24927961

Rivaroxaban modulates electrical and mechanical characteristics of left atrium

PubMed Central

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

Genome-Wide Investigation and Expression Profiling of AP2/ERF Transcription Factor Superfamily in Foxtail Millet (Setaria italica L.)

PubMed Central

Lata, Charu; Mishra, Awdhesh Kumar; Muthamilarasan, Mehanathan; Bonthala, Venkata Suresh; Khan, Yusuf; Prasad, Manoj

2014-01-01

The APETALA2/ethylene-responsive element binding factor (AP2/ERF) family is one of the largest transcription factor (TF) families in plants that includes four major sub-families, namely AP2, DREB (dehydration responsive element binding), ERF (ethylene responsive factors) and RAV (Related to ABI3/VP). AP2/ERFs are known to play significant roles in various plant processes including growth and development and biotic and abiotic stress responses. Considering this, a comprehensive genome-wide study was conducted in foxtail millet (Setaria italica L.). A total of 171 AP2/ERF genes were identified by systematic sequence analysis and were physically mapped onto nine chromosomes. Phylogenetic analysis grouped AP2/ERF genes into six classes (I to VI). Duplication analysis revealed that 12 (∼7%) SiAP2/ERF genes were tandem repeated and 22 (∼13%) were segmentally duplicated. Comparative physical mapping between foxtail millet AP2/ERF genes and its orthologs of sorghum (18 genes), maize (14 genes), rice (9 genes) and Brachypodium (6 genes) showed the evolutionary insights of AP2/ERF gene family and also the decrease in orthology with increase in phylogenetic distance. The evolutionary significance in terms of gene-duplication and divergence was analyzed by estimating synonymous and non-synonymous substitution rates. Expression profiling of candidate AP2/ERF genes against drought, salt and phytohormones revealed insights into their precise and/or overlapping expression patterns which could be responsible for their functional divergence in foxtail millet. The study showed that the genes SiAP2/ERF-069, SiAP2/ERF-103 and SiAP2/ERF-120 may be considered as potential candidate genes for further functional validation as well for utilization in crop improvement programs for stress resistance since these genes were up-regulated under drought and salinity stresses in ABA dependent manner. Altogether the present study provides new insights into evolution, divergence and systematic functional analysis of AP2/ERF gene family at genome level in foxtail millet which may be utilized for improving stress adaptation and tolerance in millets, cereals and bioenergy grasses. PMID:25409524

Genome-wide investigation and expression profiling of AP2/ERF transcription factor superfamily in foxtail millet (Setaria italica L.).

PubMed

Lata, Charu; Mishra, Awdhesh Kumar; Muthamilarasan, Mehanathan; Bonthala, Venkata Suresh; Khan, Yusuf; Prasad, Manoj

2014-01-01

The APETALA2/ethylene-responsive element binding factor (AP2/ERF) family is one of the largest transcription factor (TF) families in plants that includes four major sub-families, namely AP2, DREB (dehydration responsive element binding), ERF (ethylene responsive factors) and RAV (Related to ABI3/VP). AP2/ERFs are known to play significant roles in various plant processes including growth and development and biotic and abiotic stress responses. Considering this, a comprehensive genome-wide study was conducted in foxtail millet (Setaria italica L.). A total of 171 AP2/ERF genes were identified by systematic sequence analysis and were physically mapped onto nine chromosomes. Phylogenetic analysis grouped AP2/ERF genes into six classes (I to VI). Duplication analysis revealed that 12 (∼7%) SiAP2/ERF genes were tandem repeated and 22 (∼13%) were segmentally duplicated. Comparative physical mapping between foxtail millet AP2/ERF genes and its orthologs of sorghum (18 genes), maize (14 genes), rice (9 genes) and Brachypodium (6 genes) showed the evolutionary insights of AP2/ERF gene family and also the decrease in orthology with increase in phylogenetic distance. The evolutionary significance in terms of gene-duplication and divergence was analyzed by estimating synonymous and non-synonymous substitution rates. Expression profiling of candidate AP2/ERF genes against drought, salt and phytohormones revealed insights into their precise and/or overlapping expression patterns which could be responsible for their functional divergence in foxtail millet. The study showed that the genes SiAP2/ERF-069, SiAP2/ERF-103 and SiAP2/ERF-120 may be considered as potential candidate genes for further functional validation as well for utilization in crop improvement programs for stress resistance since these genes were up-regulated under drought and salinity stresses in ABA dependent manner. Altogether the present study provides new insights into evolution, divergence and systematic functional analysis of AP2/ERF gene family at genome level in foxtail millet which may be utilized for improving stress adaptation and tolerance in millets, cereals and bioenergy grasses.

Advanced APS impacts on vehicle payloads

NASA Technical Reports Server (NTRS)

Schneider, Steven J.; Reed, Brian D.

1989-01-01

Advanced auxiliary propulsion system (APS) technology has the potential to both, increase the payload capability of earth-to-orbit (ETO) vehicles by reducing APS propellant mass, and simplify ground operations and logistics by reducing the number of fluids on the vehicle and eliminating toxic, corrosive propellants. The impact of integrated cryogenic APS on vehicle payloads is addressed. In this system, launch propulsion system residuals are scavenged from integral launch propulsion tanks for use in the APS. Sufficient propellant is preloaded into the APS to return to earth with margin and noncomplete scavenging assumed. No propellant conditioning is required by the APS, but ambient heat soak is accommodated. High temperature rocket materials enable the use of the unconditioned hydrogen/oxygen in the APS and are estimated to give APS rockets specific impulse of up to about 444 sec. The payload benefits are quantified and compared with an uprated monomethylhydrazine/nitrogen tetroxide system in a conservative fashion, by assuming a 25.5 percent weight growth for the hydrogen/oxygen system and a 0 percent weight growth for the uprated system. The combination of scavenging and high performance gives payload impacts which are highly mission specific. A payload benefit of 861 kg (1898 lbm) was estimated for a Space Station Freedom rendezvous mission and 2099 kg (4626 lbm) for a sortie mission, with payload impacts varying with the amount of launch propulsion residual propellants. Missions without liquid propellant scavenging were estimated to have payload penalties, however, operational benefits were still possible.

Advanced APS Impacts on Vehicle Payloads

NASA Technical Reports Server (NTRS)

Schneider, Steven J.; Reed, Brian D.

1989-01-01

Advanced auxiliary propulsion system (APS) technology has the potential to both, increase the payload capability of earth-to-orbit (ETO) vehicles by reducing APS propellant mass, and simplify ground operations and logistics by reducing the number of fluids on the vehicle and eliminating toxic, corrosive propellants. The impact of integrated cryogenic APS on vehicle payloads is addressed. In this system, launch propulsion system residuals are scavenged from integral launch propulsion tanks for use in the APS. Sufficient propellant is preloaded into the APS to return to earth with margin and noncomplete scavenging assumed. No propellant conditioning is required by the APS, but ambient heat soak is accommodated. High temperature rocket materials enable the use of the unconditioned hydrogen/oxygen in the APS and are estimated to give APS rockets specific impulse of up to about 444 sec. The payload benefits are quantified and compared with an uprated monomethyl hydrazine/nitrogen tetroxide system in a conservative fashion, by assuming a 25.5 percent weight growth for the hydrogen/oxygen system and a 0 percent weight growth for the uprated system. The combination and scavenging and high performance gives payload impacts which are highly mission specific. A payload benefit of 861 kg (1898 lbm) was estimated for a Space Station Freedom rendezvous mission and 2099 kg (4626 lbm) for a sortie mission, with payload impacts varying with the amount of launch propulsion residual propellants. Missions without liquid propellant scavenging were estimated to have payload penalties, however, operational benefits were still possible.

Bacteroides fragilis Enterotoxin Induces Formation of Autophagosomes in Endothelial Cells but Interferes with Fusion with Lysosomes for Complete Autophagic Flux through a Mitogen-Activated Protein Kinase-, AP-1-, and C/EBP Homologous Protein-Dependent Pathway.

PubMed

Ko, Su Hyuk; Jeon, Jong Ik; Myung, Hyun Soo; Kim, Young-Jeon; Kim, Jung Mogg

2017-10-01

Bacteroides fragilis enterotoxin (BFT), a virulence factor of enterotoxigenic B. fragilis (ETBF), plays an essential role in mucosal inflammation. Although autophagy contributes to the pathogenesis of diverse infectious diseases, little is known about autophagy in ETBF infection. This study was conducted to investigate the role of BFT in the autophagic process in endothelial cells (ECs). Stimulation of human umbilical vein ECs (HUVECs) with BFT increased light chain 3 protein II (LC3-II) conversion from LC3-I and protein expression of p62, Atg5, and Atg12. In addition, BFT-exposed ECs showed increased indices of autophagosomal fusion with lysosomes such as LC3-lysosome-associated protein 2 (LAMP2) colocalization and the percentage of red vesicles monitored by the expression of dual-tagged LC3B. BFT also upregulated expression of C/EBP homologous protein (CHOP), and inhibition of CHOP significantly increased indices of autophagosomal fusion with lysosomes. BFT activated an AP-1 transcription factor, in which suppression of AP-1 activity significantly downregulated CHOP and augmented autophagosomal fusion with lysosomes. Furthermore, suppression of Jun N-terminal protein kinase (JNK) mitogen-activated protein kinase (MAPK) significantly inhibited the AP-1 and CHOP signals, leading to an increase in autophagosomal fusion with lysosomes in BFT-stimulated ECs. These results suggest that BFT induced accumulation of autophagosomes in ECs, but activation of a signaling pathway involving JNK, AP-1, and CHOP may interfere with complete autophagy. Copyright © 2017 American Society for Microbiology.

Determinants of muscle metaboreflex and involvement of baroreflex in boys and young men.

PubMed

Dipla, Konstantina; Papadopoulos, Stavros; Zafeiridis, Andreas; Kyparos, Antonios; Nikolaidis, Michalis G; Vrabas, Ioannis S

2013-04-01

This study aimed to assess the arterial pressure (AP) determinants during the muscle metaboreflex in boys and men and to investigate the contribution of baroreflex and sympathovagal function to the metaboreflex-induced responses. Fourteen pre-adolescent boys and 13 men performed a protocol involving: baseline, isometric handgrip exercise, circulatory occlusion, and recovery. The same protocol was repeated without occlusion. During baseline, boys had lower beat-to-beat AP, higher heart rate (HR), and lower low/high frequency HR variability. During exercise, a parasympathetic withdrawal was evident in both groups. In adults, HR was the key contributor to the pressure response, with no changes in stroke volume, whereas in boys, the lower HR increase was counterbalanced by an increase in stroke volume, resulting in similar relative increases in AP in both groups. In recovery, boys exhibited a faster rate of HR-decay, rapid vagal reactivation, and greater decrease in TPR than men. An overshoot in baroreceptor sensitivity was observed in men. The isolated metaboreflex resulted in a similar AP elevation in both age groups (by ~15 mmHg), and attenuated spontaneous baroreceptor sensitivity. However, during the metaboreflex, pre-adolescent males exhibited a lower increase in peripheral resistance and a greater bradycardic response than adults, and a fast restoration of vagal activity to non-occlusion levels. During metaboreflex, boys were capable of eliciting a pressure response similar to the one elicited by men; however, the interplay of the mechanisms underlying the rise in AP differed between the two groups with the vagal contribution being greater in the younger participants.

[Study of Staphylococcus aureus infections in a general acute care hospital (2002-2013)].

PubMed

Togneri, Ana M; Podestá, Laura B; Pérez, Marcela P; Santiso, Gabriela M

A twelve-year retrospective review of Staphylococcus aureus infections in adult and pediatric patients (AP and PP respectively) assisted in the Hospital Interzonal General de Agudos Evita in Lanús was performed to determine the incidence, foci of infection, the source of infection and to analyze the profile of antimicrobial resistance. An amount of 2125 cases of infection in AP and 361 in PP were documented. The incidence in AP decreased significantly in the last three years (χ i 2 ; p<0.05); in PP it increased significantly during the last five years (χ 2 ; p<0.0001). In both populations was detected a notable increase in skin infections and associated structures (PEA) in bacteremia to the starting point of a focus on PEA, and in total S. aureus infections of hospital-onset (χ 2 ; p < 0.005). Methicillin-resistance (MRSA) increased from 28 to 78% in PP; in AP it remained around 50%, with significant reduction in accompanying antimicrobial resistance to non-β-lactams in both groups of MRSA. In S. aureus documented from community onset infections (CO-MRSA) in the last three years, the percentage of methicillin-resistance was 57% in PP and 37% in AP; in hospital-onset infections it was 43% and 63% respectively. Although data showed that S. aureus remains a pathogen associated with the hospital-onset, there was an increase of CO-MRSA infections with predominance in PEA in both populations. Copyright © 2016 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Enhanced production of leech hyaluronidase by optimizing secretion and cultivation in Pichia pastoris.

PubMed

Kang, Zhen; Zhang, Na; Zhang, Yunfeng

2016-01-01

Leech hyaluronidase (LHAase) was recently cloned and successfully expressed in Pichia pastoris. To increase its secretory expression level, four signal peptides (nsB, YTP1, SCS3, and HKR1) and six amphipathic peptides (APs) were comparatively investigated. After substitution with nsB and fusion with AP2, the production of LHAase was significantly increased, from 8.42 × 10(5) to 1.24 × 10(6) U/ml. Compared with the parental LHAase, the variant AP2-LHAase showed a lower optimum pH (5.0), higher optimum temperature (50 °C), and a broader range of thermal stability (20-60 °C). To further promote fermentative production of the variant AP2-LHAase, the cultivation temperature was systematically optimized according to cell viability and alcohol oxidase activity. Eventually, through a combination of N-terminal engineering and optimization of cultivation, the production of LHAase was improved to 1.68 × 10(6) U/ml, with a high productivity of 1.87 × 10(4) U/ml/h.

The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

PubMed Central

Garces de los Fayos Alonso, Ines; Lagger, Sabine; Merkel, Olaf; Kenner, Lukas

2018-01-01

The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma. PMID:29597249

Links between Adolescents’ Closeness to Adoptive Parents and Attachment Style in Young Adulthood

PubMed Central

Grant-Marsney, Holly A.; Grotevant, Harold D.; Sayer, Aline G.

2014-01-01

This study examined whether adolescents’ closeness to adoptive parents (APs) predicted attachment styles in close relationships outside their family during young adulthood. In a longitudinal study of domestic infant adoptions, closeness to adoptive mother and adoptive father was assessed in 156 adolescents (M = 15.7 years). Approximately nine years later (M = 25.0 years), closeness to parents was assessed again as well as attachment style in their close relationships. Multilevel modeling was used to predict attachment style in young adulthood from the average and discrepancy of closeness to adolescents’ adoptive mothers and fathers and the change over time in closeness to APs. Less avoidant attachment style was predicted by stronger closeness to both APs during adolescence. Increased closeness to APs over time was related to less anxiety in close relationships. Higher closeness over time to either AP was related to less avoidance and anxiety in close relationships. PMID:25859067

Links between Adolescents' Closeness to Adoptive Parents and Attachment Style in Young Adulthood.

PubMed

Grant-Marsney, Holly A; Grotevant, Harold D; Sayer, Aline G

2015-04-01

This study examined whether adolescents' closeness to adoptive parents (APs) predicted attachment styles in close relationships outside their family during young adulthood. In a longitudinal study of domestic infant adoptions, closeness to adoptive mother and adoptive father was assessed in 156 adolescents ( M = 15.7 years). Approximately nine years later ( M = 25.0 years), closeness to parents was assessed again as well as attachment style in their close relationships. Multilevel modeling was used to predict attachment style in young adulthood from the average and discrepancy of closeness to adolescents' adoptive mothers and fathers and the change over time in closeness to APs. Less avoidant attachment style was predicted by stronger closeness to both APs during adolescence. Increased closeness to APs over time was related to less anxiety in close relationships. Higher closeness over time to either AP was related to less avoidance and anxiety in close relationships.

Air Pollution, Oxidative Stress, and Alzheimer's Disease

PubMed Central

Moulton, Paula Valencia; Yang, Wei

2012-01-01

Alzheimer's disease (AD) is the most common form of dementia affecting millions of people worldwide and will continue to affect millions more with population aging on the rise. AD causality is multifactorial. Known causal factors include genetic predisposition, age, and sex. Environmental toxins such as air pollution (AP) have also been implicated in AD causation. Exposure to AP can lead to chronic oxidative stress (OS), which is involved in the pathogenesis of AD. Whereas AP plays a role in AD pathology, the epidemiological evidence for this association is limited. Given the significant prevalence of AP exposure combined with increased population aging, epidemiological evidence for this link is important to consider. In this paper, we examine the existing evidence supporting the relationship between AP, OS, and AD and provide recommendations for future research on the population level, which will provide evidence in support of public health interventions. PMID:22523504

Microelectrode array measurement of potassium ion channel remodeling on the field action potential duration in rapid atrial pacing rabbits model.

PubMed

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.

Actions of arginine polyamine on voltage and ligand-activated whole cell currents recorded from cultured neurones.

PubMed

Scott, R H; Sweeney, M I; Kobrinsky, E M; Pearson, H A; Timms, G H; Pullar, I A; Wedley, S; Dolphin, A C

1992-05-01

1. Toxins from invertebrates have proved useful tools for investigation of the properties of ion channels. In this study we describe the actions of arginine polyamine which is believed to be a close analogue of FTX, a polyamine isolated from the American funnel web spider, Agelenopsis aperta. 2. Voltage-activated Ca2+ currents and Ca(2+)-dependent Cl- currents recorded from rat cultured dorsal root ganglion neurones were reversibly inhibited by arginine polyamine (AP; 0.001 to 100 microM). Low voltage-activated T-type Ca2+ currents were significantly more sensitive to AP than high voltage-activated Ca2+ currents. The IC50 values for the actions of AP on low and high voltage-activated Ca2+ currents were 10 nM and 3 microM respectively. AP was equally effective in inhibiting high voltage-activated currents carried by Ba2+, Sr2+ or Ca2+. However, AP-induced inhibition of Ca2+ currents was attenuated by increasing the extracellular Ca2+ concentration from 2 mM to 10 mM. 3. The actions of AP on a Ca(2+)-independent K+ current were more complex, 1 microM AP enhanced this current but 10 microM AP had a dual action, initially enhancing but then inhibiting the K+ current. 4. gamma-Aminobutyric acid-activated Cl- currents were also reversibly inhibited by 1 to 10 microM AP. In contrast N-methyl-D-aspartate currents recorded from rat cultured cerebellar neurones were greatly enhanced by 10 microM AP. 5. We conclude that at a concentration of 10 nM, AP is a selective inhibitor of low threshold T-type voltage-activated Ca2+ currents. However, at higher concentrations 1-10 microM AP interacts with ion channels or other membrane constituents to produce a variety of actions on both voltage and ligand gated ion channels.

Genome-Wide Identification of AP2/ERF Transcription Factors in Cauliflower and Expression Profiling of the ERF Family under Salt and Drought Stresses

PubMed Central

Li, Hui; Wang, Yu; Wu, Mei; Li, Lihong; Li, Cong; Han, Zhanpin; Yuan, Jiye; Chen, Chengbin; Song, Wenqin; Wang, Chunguo

2017-01-01

The AP2/ERF transcription factors (TFs) comprise one of the largest gene superfamilies in plants. These TFs perform vital roles in plant growth, development, and responses to biotic and abiotic stresses. In this study, 171 AP2/ERF TFs were identified in cauliflower (Brassica oleracea L. var. botrytis), one of the most important horticultural crops in Brassica. Among these TFs, 15, 9, and 1 TFs were classified into the AP2, RAV, and Soloist family, respectively. The other 146 TFs belong to ERF family, which were further divided into the ERF and DREB subfamilies. The ERF subfamily contained 91 TFs, while the DREB subfamily contained 55 TFs. Phylogenetic analysis results indicated that the AP2/ERF TFs can be classified into 13 groups, in which 25 conserved motifs were confirmed. Some motifs were group- or subgroup- specific, implying that they are significant to the functions of the AP2/ERF TFs of these clades. In addition, 35 AP2/ERF TFs from the 13 groups were selected randomly and then used for expression pattern analysis under salt and drought stresses. The majority of these AP2/ERF TFs exhibited positive responses to these stress conditions. In specific, Bra-botrytis-ERF054a, Bra-botrytis-ERF056, and Bra-botrytis-CRF2a demonstrated rapid responses. By contrast, six AP2/ERF TFs were showed to delay responses to both stresses. The AP2/ERF TFs exhibiting specific expression patterns under salt or drought stresses were also confirmed. Further functional analysis indicated that ectopic overexpression of Bra-botrytis-ERF056 could increase tolerance to both salt and drought treatments. These findings provide new insights into the AP2/ERF TFs present in cauliflower, and offer candidate AP2/ERF TFs for further studies on their roles in salt and drought stress tolerance. PMID:28642765