Refractory Phenomenon Research Articles

Intracoronary epinephrine and verapamil in the refractory no-reflow phenomenon in patients with acute myocardial infarction

Despite modern advances in performing percutaneous coronary interventions, refractory no-reflow remains a serious problem that worsens in-hospital and long-term prognosis. Low-dose adrenaline may exhibit potent beta-receptor agonist properties that mediate coronary vasodilation.Aim. To evaluate the efficacy and safety of intracoronary administration of epinephrine and verapamil, as well as their combination, compared with standard treatment in patients with ST-segment elevation myocardial infarction (STEMI) and refractory no-reflow during percutaneous coronary interventions.Material and methods. Patients with STEMI and refractory no-reflow will be randomized into 4 groups: standard therapy, intracoronary adrenaline, intracoronary verapamil, intracoronary epinephrine + verapamil. All patients will be assessed for epicardial blood flow using the Thrombolysis in Myocardial Infarction (TIMI) and Myocardial Blush Grade (MBG) scales, peak troponin levels, ST segment changes, echocardiography, magnetic roesnance imaging, and dynamic single photon emission computed tomography.Results. Based on the pharmacodynamic effects of epinephrine and verapamil, their combination is expected to have a more potent vasodilating effect.Conclusion. If the Intracoronary administration of EPInephrine and VERapamil in the refractory no-reflow phenomenon (EPIVER) study will be successful, a novel, more effective method for managing refractory no-reflow phenomenon will appear. This will ensure better preservation of left ventricular systolic function, as well as improve the prognosis and clinical course of the disease.

Anomalous refraction of optical spacetime wave packets

Refraction at the interface between two materials is fundamental to the interaction of light with photonic devices and to the propagation of light through the atmosphere at large. Underpinning the traditional rules for the refraction of an optical field is the tacit presumption of the separability of its spatial and temporal degrees-of-freedom. We show here that endowing a pulsed beam with precise spatio-temporal spectral correlations unveils remarkable refractory phenomena, such as group-velocity invariance with respect to the refractive index, group-delay cancellation, anomalous group-velocity increase in higher-index materials, and tunable group velocity by varying the angle of incidence. A law of refraction for `space-time' wave packets encompassing these effects is verified experimentally in a variety of optical materials. Space-time refraction defies our expectations derived from Fermat's principle and offers new opportunities for molding the flow of light and other wave phenomena.

A Model for Single Neuron Activity With Refractory Effects and Spike Rate Estimation Techniques.

The use of random point processes as models for neural spike trains allows the derivation of powerful statistical estimation techniques for time varying firing rates. Frequently, however, such estimators are based on the assumption that spike sequences follow a Poisson point process. Because of the bio-physical properties of neuronal action potentials, spike trains are affected by the refractory phenomenon that induces history dependency, and hence contradicts the Poisson assumption. In this work we present a neural spiking model, and a Maximum Likelihood (ML) estimation framework for time varying firing rates, that account for history dependencies in spike trains. Our framework is based on an exponential of polynomial model for the excitation function (stimulus), that generates a self exciting point process representing spike trains with absolute as well as relative refractory effects. Using this framework we employ techniques based on non-convex optimization and model order selection to derive ML estimators for neuronal firing rates. Results on simulated data with a refractory period show an improvement in accuracy when our estimation technique, that accounts for the complete refractory phenomenon, is used. Employing this estimation method for measured neuronal data shows an improvement in goodness of fit over estimators that do not account for the refractory effect, and also over other commonly used techniques.

Evoked bioelectrical activity of efferent fibers of the sciatic nerve of white rats in experimental menopause.

The aim of our work was analysis of the bioelectrical activity of efferent fibers of the sciatic nerve in experimental menopause condition. Experiments were performed on 25 female white rats, divided into experimental and control groups. Menopause was modeled by total ovariohysterectomy. In 120 days after modeling we had recorded evoked action potentials of fibers of isolated ventral root L5 induced by stimulation of sciatic nerve with rectangular pulses. Threshold, chronaxia, latency, amplitude and duration of the action potential (AP) were analysed. Refractory phenomenon was investigated by applying paired stimuli at intervals of 2 to 20 ms. In the context of long-term hypoestrogenemy threshold of AP appearance was 55,32±7,69%, chronaxy – 115,09±2,67%, latent period – 112,62±1,74% as compared with the control animals (p<0.01). In conditions of paired stimuli applying the amplitude of response to the testing stimulus in animals with ovariohysterectomy at intervals 3 and 4 ms was 61,25±36,45% and 53,48±18,64% (p<0.05) respectively.

The Pro-inflammatory Cytokine Interleukin-1β is a Key Regulatory Factor for the Postictal Suppression in Mice.

The postictal suppression (PS) is a common and important period following an epileptic seizure but has not been well studied. This study was designed to determine whether interleukin-1β (IL-1β) is involved in the PS. The effects of IL-1β on the PS were tested in three independent seizure models induced by hippocampal kindling, maximal electroshock seizure (MES), and 4-aminopyridine, respectively. IL-1R1 knockout or IL-1RA enhanced the seizure refractory phenomenon without influencing the baseline seizure threshold in intermittent MES model. IL-1β attenuated the seizure refractory phenomenon without affecting the severity of the preceding seizures in hippocampal kindling model, while IL-1RA enhanced it. Besides, IL-1β reduced the postictal EEG suppression period, while IL-1RA prolonged it. And IL-1β showed no further effect on the postictal EEG suppression and seizure refractory phenomenon in IL-1R1 knockout mice. In addition, 30 min after intrahippocampal injection of 4-aminopyridine, IL-1β increased the incidence of SE, while IL-1RA prolonged the intervals between recurrent seizures. This study provides the first direct evidence that IL-1β is key regulatory factor for the PS, and its receptor IL-1R1 may be a potential target for adjuvant treatment of postictal problems.

The “nervous” kidney and ventricular fibrillation: A possible game changer?

The “nervous” kidney and ventricular fibrillation: A possible game changer?

Hematopoietic modulators as potential agents for the treatment of leukemia

Leukemias are the most common malignancy of childhood and have the highest mortality among aging people. Leukemias are a group of blood disorders characterized by an accumulation of leukemic cells in the peripheral blood of patients as a result of disturbances in proliferation and differentiation. Refractory leukemia remains the most common therapeutic challenge. In recent years, the presence of a cancer stem cell population in leukemias has been proposed as a cause for the refractory phenomenon. Insights into the cellular and molecular features of leukemia led to a new point of view in the choice of novel therapeutic agents. New agents for the treatment of this disease should selectively target leukemia stem cells or exhibit higher cytotoxic effects in cancer cells than in normal cells. A special interest is focused on anticancer agents from biological and natural sources that can be used in the treatment of leukemia. This review discusses the characteristics of some of these potential new agents.

Postrepolarization refractoriness: A mechanism in need for a molecule?

In this issue of HeartRhythm, an unusual and very interesting contemporary review article 1 Coronel R. Janse M. Opthof T. Wilde A. Taggart P. Postrepolarization refractoriness in acute ischemia and after antiarrhythmic drug administration: action potential duration is not always an index of the refractory period. Heart Rhythm. 2012; 9: 977-982 Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar can be found. The list of authors already generates curiosity, spanning 3 generations of electrophysiologists, from pioneers of action potential measurements in large animals and in patients undergoing open heart surgery to experts in “genetic electrophysiology” in patients and mice with genetically conferred cardiomyopathies. These experts chose to review postrepolarization refractoriness and to discuss the current knowledge on postrepolarization refractoriness and its involvement in causing and preventing arrhythmias with a focus on arrhythmogenesis in the acutely ischemic heart. The review reminds us of one of the fundamental concepts in electrophysiology, the relation between refractoriness and repolarization, and how altering this relation can have pro- and antiarrhythmic effects. Postrepolarization refractoriness in acute ischemia and after antiarrhythmic drug administration: Action potential duration is not always an index of the refractory periodHeart RhythmVol. 9Issue 6PreviewAction potential duration is widely used as a measure of refractory period in ischemia. Although the end of repolarization closely corresponds to the end of refractoriness in the well-perfused, well-oxygenated myocardium, it is no longer true for the ischemic myocardium, in which the recovery of excitability lags behind full repolarization. The purpose the study was to review this phenomenon of postrepolarization refractoriness during ischemia and after application of various antiarrhythmic drugs. Full-Text PDF

Postrepolarization refractoriness in acute ischemia and after antiarrhythmic drug administration: Action potential duration is not always an index of the refractory period

Action potential duration is widely used as a measure of refractory period in ischemia. Although the end of repolarization closely corresponds to the end of refractoriness in the well-perfused, well-oxygenated myocardium, it is no longer true for the ischemic myocardium, in which the recovery of excitability lags behind full repolarization. The purpose the study was to review this phenomenon of postrepolarization refractoriness during ischemia and after application of various antiarrhythmic drugs. The findings showed that although postrepolarization refractoriness is profoundly proarrhythmic during ischemia, it may protect the heart from reentrant arrhythmias in the absence of depolarization of the resting membrane. An increase in postrepolarization refractoriness induced by sodium-channel-blocking drugs may exert an antifibrillatory action.

Refractoriness and the healthy brain: A behavioural study on semantic access

While many behavioural studies on refractory phenomena in lexical/semantic access have focused on the mechanisms involved in the oral production of names, comprehension tasks have been almost exclusively used in neuropsychological studies on brain damaged patients. We report the results of two experiments on healthy participants conducted by means of speeded word to picture matching tasks. They assess the effects of the same variables examined in the study of refractory access dysphasic patients: semantic distance and word frequency (experiment 1) and presentation rate and serial position effects (experiment 2). Semantic access patients usually show little effect of word frequency but a large semantic distance effect. However, critical in characterising the syndrome as ‘refractory’, effects of presentation rate and serial position should also be present. The experiments involved the use of a deadline response procedure. The critical manipulation was the absence of a Response Stimulus Interval (RSI) in the fast presentation rate conditions; slower presentation rates involved 1 s RSI. With these manipulations the typical behavioural pattern of performance provided by semantic access dysphasic patients was reproduced. Semantic distance effects were more powerful than word frequency effects (experiment1). Presentation rate effects were found and, most important for a “refractory” account of the effects, a serial position effect was obtained (experiment 2). These results provide the first evidence of such a broad range of refractory effects at the same time in comprehension tasks in healthy subjects and support a purely semantic account for the locus of refractoriness. Moreover, error analysis showed a predominance of perseverative errors with subsequent representations of the same target, supporting a failure of cognitive control mechanisms as the cause of refractory behaviour. The findings are discussed in the light of current models of lexical and semantic processing.

Postcardiotomy Extracorporeal Life Support in Adults: The Optimal Duration of Bridging to Recovery

Extracorporeal life support (ECLS) is a temporary support of postcardiotomy cardiogenic shock (PCS). Mortality of postcardiotomy ECLS often results from inability to recognize appropriate patients and bridge them to the next therapy before complications. A two-gated strategy for the second bridge transferring was suggested. From January 2003 to January 2008, 72 patients (mean 60 years) received ECLS for PCS. Indicators of cardiac recovery were identified from the physiological responses to ECLS. The optimal ECLS duration for myocardial recovery was defined as the supporting time of survivors. Forty-one patients weaned off ECLS and 29 survived to discharge. The mean duration of ECLS was 130 hours. Twenty- eight of the 29 survivors weaned off ECLS within 7 days. ECLS >100 hours and a refractory phenomenon of persistent hypotension (mean arterial pressure < 70 mm Hg) with a high adrenergic demand (inotropic equivalent score > 35) under a sufficient ECLS (flow > 50 ml x kg x min, SvO(2) > 80%) >24 hours were independent risk factors of ECLS nonweaning. The benefits of adult postcardiotomy ECLS are controversial after a 7-day support. Bridging should be considered in suitable patients having ECLS >7 days or showing instabilities under an adequate ECLS >24 hours. Continuing ECLS poses a higher risk of mortality.

Automatic Estimation of the Dynamics of Channel Conductance Using a Recurrent Neural Network

In order to simulate neuronal electrical activities, we must estimate the dynamics of channel conductances from physiological experimental data. However, this approach requires the formulation of differential equations that express the time course of channel conductance. On the other hand, if the dynamics are automatically estimated, neuronal activities can be easily simulated. By using a recurrent neural network (RNN), it is possible to estimate the dynamics of channel conductances without formulating the differential equations. In the present study, we estimated the dynamics of the Na+ and K+ conductances of a squid giant axon using two different fully connected RNNs and were able to reproduce various neuronal activities of the axon. The reproduced activities were an action potential, a threshold, a refractory phenomenon, a rebound action potential, and periodic action potentials with a constant stimulation. RNNs can be trained using channels other than the Na+ and K+ channels. Therefore, using our RNN estimation method, the dynamics of channel conductance can be automatically estimated and the neuronal activities can be simulated using the channel RNNs. An RNN can be a useful tool to estimate the dynamics of the channel conductance of a neuron, and by using the method presented here, it is possible to simulate neuronal activities more easily than by using the previous methods.

Refractoriness of UVA-induced Protection from Photoimmunosuppression Correlates with Heme Oxygenase Response to Repeated UVA Exposure¶

Single suberythemal exposures of UVA radiation have been shown to block the immunosuppressive effects of UVB radiation in the mouse. The immunoprotection is dependent both on the presence of the cytokine, IFN-γ, and on the induction of the antioxidant stress enzyme, heme oxygenase (HO), in the skin. Recently, the transcriptional response of the HO-1 gene to UVA radiation in cultured human skin fibroblasts was reported to be refractory to a second UVA irradiation. In this study on the hairless mouse, we demonstrate that the inducibility of HO enzyme activity in the skin similarly became refractory to a second UVA irradiation at 24 h but, like the fibroblast response, was restored when the interval between the UVA exposures was increased to 96 h. Under the conditions of refractory HO enzyme induction, the protective effect of UVA radiation against the suppression of contact hypersensitivity induced by UVB radiation or cis-urocanic acid was strongly attenuated but was restored when the interval between UVA exposures was increased to 96 h. The results thus confirm the strong relationship between HO induction and photoimmunoprotection by UVA radiation, and describe a new phenomenon of immunological refractoriness that develops with rapidly repeated UVA exposures.

Ca2+ transient induced by extracellular changes in osmotic pressure in Arabidopsis leaves: differential involvement of cell wall–plasma membrane adhesion

We investigated the mechanism underlying the perception of extracellular changes in osmotic pressure in Vallisneria gigantea Graebner and transgenic Arabidopsis thaliana (L.) Heynh. expressing cytoplasmic aequorin. Hypertonic and hypotonic treatments of A. thaliana leaves each rapidly induced a Ca2+ transient. Both responses were essentially dependent on the presence of extracellular Ca2+ and were sensitive to Gd3+ a potential blocker of stretch-activated Ca2+ channels. Immediately after plasmolysis caused by hypertonic treatment and subsequent deplasmolysis caused by hypotonic treatment, the cells did not respond to a second hypertonic treatment and exhibited an impaired adhesion of the plasma membrane (PM) to the cell wall (CW). Recovery of the responsiveness required about 6 h. By contrast, no refractory phenomenon was observed in response to hypotonic treatment. Pretreatment with cellulase completely inhibited the Ca2+ transient induced by hypertonic treatment, but it did not affect the response to hypotonic treatment. V. gigantea mesophyll cells pretreated with cellulase exhibited an impaired adhesion of the PM to the CW. The leaf cells of multicellular plants can respond to both hypertonic and hypotonic treatments through the stretch-activated Ca2+ channels, whereas cellulase-sensitive adhesion of the PM to the CW is involved only in the response to hypertonic treatment.

Adoptive Transfer of Mast Cells Abolishes the Inflammatory Refractoriness to Allergen in Diabetic Rats

Mast cells are pivotal secretory cells primarily implicated in allergen-evoked inflammatory responses and are downregulated following experimental chemical diabetes. Here we tested the hypothesis that a decrease in the number and reactivity of mast cells would account for the hyporesponsiveness of diabetic rats to allergen-induced inflammation. We found that the anaphylactic release of histamine from sensitized ileum, trachea and skin tissues was clearly reduced in rats turned diabetic via intravenous administration of alloxan. Likewise, actively and passively sensitized diabetic rats mounted a weaker allergen-evoked pleural mast cell degranulation and protein extravasation, as compared to sensitized nondiabetic animals, which paralleled a marked reduction in the mast cell population in the pleural cavity. The number of mast cells enumerated in the mesentery from diabetic rats was also clearly reduced. The allergen-evoked plasma leakage in diabetic rats was restored by the transfer of mast cells from sensitized nondiabetic rats. Moreover, the adoptive transfer of sensitized mast cells from diabetics to naive animals led to a lower allergen-induced exudation as compared to the response noted after the transfer of sensitized naive mast cells. Purified mast cells from diabetic rats were hyporesponsive to antigen and compound 48/80 stimulation in vitro as attested by histamine release. Thus, our results show that the phenomenon of refractoriness of diabetic animals to allergen challenge appears to be accounted for by a reduction in the number and reactivity of mast cells.

Ca2+ Dynamics during Membrane Excitation of Green Alga Chara: Model Simulations and Experimental Data

Kinetic investigations of stimulus response coupling in the green alga Chara have revealed that an intermediate second messenger is formed in the process of membrane excitation. This second messenger links electrical stimulation to the mobilization of Ca2+ from internal stores. In the present work, the experimentally based kinetic model, which describes the stimulus-dependent production of the second messenger and Ca2+ mobilization, is combined with a model for inositol 1,4,5-trisphosphate (IP3)-and Ca2+-sensitive gating of a Ca2+-release channel in endomembranes of animal cells. The combination of models allows a good simulation of experimental data, including the all-or-none-type dependence of the Ca2+ response on stimulus duration and complex phase locking phenomena for the dependence of the Ca2+ response on stimulation frequency. The model offers a molecular explanation for the refractory phenomenon in Chara, assigning it to the life time of an inactive state of the Ca2+-release channel. The model furthermore explains the steep dependence of excitation on strength/duration of electrical stimulation as a consequence of an interplay of the dynamical variables in the model.

Refractoriness of UVA-induced protection from photoimmunosuppression correlates with heme oxygenase response to repeated UVA exposure.

Single suberythemal exposures of UVA radiation have been shown to block the immunosuppressive effects of UVB radiation in the mouse. The immunoprotection is dependent both on the presence of the cytokine, IFN-gamma, and on the induction of the antioxidant stress enzyme, heme oxygenase (HO), in the skin. Recently, the transcriptional response of the HO-1 gene to UVA radiation in cultured human skin fibroblasts was reported to be refractory to a second UVA irradiation. In this study on the hairless mouse, we demonstrate that the inducibility of HO enzyme activity in the skin similarly became refractory to a second UVA irradiation at 24 h but, like the fibroblast response, was restored when the interval between the UVA exposures was increased to 96 h. Under the conditions of refractory HO enzyme induction, the protective effect of UVA radiation against the suppression of contact hypersensitivity induced by UVB radiation or cis-urocanic acid was strongly attenuated but was restored when the interval between UVA exposures was increased to 96 h. The results thus confirm the strong relationship between HO induction and photoimmunoprotection by UVA radiation, and describe a new phenomenon of immunological refractoriness that develops with rapidly repeated UVA exposures.

An approach to probe some neural systems interaction by functional MRI at neural time scale down to milliseconds.

In this paper, we demonstrate an approach by which some evoked neuronal events can be probed by functional MRI (fMRI) signal with temporal resolution at the time scale of tens of milliseconds. The approach is based on the close relationship between neuronal electrical events and fMRI signal that is experimentally demonstrated in concurrent fMRI and electroencephalographic (EEG) studies conducted in a rat model with forepaw electrical stimulation. We observed a refractory period of neuronal origin in a two-stimuli paradigm: the first stimulation pulse suppressed the evoked activity in both EEG and fMRI signal responding to the subsequent stimulus for a period of several hundred milliseconds. When there was an apparent site-site interaction detected in the evoked EEG signal induced by two stimuli that were primarily targeted to activate two different sites in the brain, fMRI also displayed signal amplitude modulation because of the interactive event. With visual stimulation using two short pulses in the human brain, a similar refractory phenomenon was observed in activated fMRI signals in the primary visual cortex. In addition, for interstimulus intervals shorter than the known latency time of the evoked potential induced by the first stimulus ( approximately 100 ms) in the primary visual cortex of the human brain, the suppression was not present. Thus, by controlling the temporal relation of input tasks, it is possible to study temporal evolution of certain neural events at the time scale of their evoked electrical activity by noninvasive fMRI methodology.

Schizophrenia-like deficits in auditory P1 and N1 refractoriness induced by the psychomimetic agent phencyclidine (PCP)

Objectives: The amplitude of the cortically generated auditory event-related potential (ERP) components P1 and N1 decreases as the interval between successive stimuli (ISI) decreases. Although the phenomenon of P1 and N1 refractoriness is well established, the underlying mechanisms are poorly understood. The present study investigates P1 and N1 refractoriness in the awake monkey in order to investigate underlying mechanisms.Methods: Auditory ERP were obtained in response to repetitive auditory stimuli presented at 5 levels of ISI between 150 ms and 9 s, prior to and following administration of the selective N-methyl-d-aspartate (NMDA) antagonist phencyclidine (PCP).Results: P1 and N1 amplitude declined in monkeys with decreasing ISI, with similar temporal characteristics to that observed in humans. PCP inhibited P1 and N1 generation at long, but not short, ISI producing a pattern similar to that recently observed in schizophrenic subjects.Conclusions: The present findings suggest that the primate P1/N1 model may be useful for investigating mechanisms underlying impaired information processing in schizophrenia, and that NMDA receptor dysfunction may play a key role in information processing dysfunction associated with schizophrenia.

Glycoprotein IIb/IIIa receptor antagonists in acute myocardial infarction and primary coronary stenting: Not always effective.

Glycoprotein IIb/IIIa antagonists have been shown to be effective in reducing thrombotic complications prior to high-risk coronary interventions. Some studies have reported improved coronary flow after abciximab in slow or no-reflow phenomenon. We report a case in which abciximab did not clear the thrombotic occlusion or restore artery flow. Further studies are needed into the refractory no-flow phenomenon.