Recovery Of Amplitude Research Articles

Attenuated Herpes simplex virus 1 vector expressing oncomodulin effectively allieviates mechanical optic nerve injury in rats

To evaluate the efficacy and safety of attenuated Herpes simplex virus 1 (HSV-1) vector expressing oncomodulin (OCM) for treatment of mechanical optic nerve injury in rats. The proliferation characteristics and OCM expression of the recombinant HSV-1 vector (1716-OCM) was assessed in cultured Vero cells. Twelve-week-old SD rats were randomly divided into control group, 1716-OCM injection group and wild-type virus corneal infection group, and at 7, 14, 30 and 60 days post-infection (3 rats in each group at each time point), the expressions of OCM and HSV-1 structural protein gB in the retina and the hypothalamus of the rats were detected using immunofluorescence assay. Another 20 rats were randomized into sham operation group, PBS treatment group, 1716-OCM infection group and 1716-OCM infection with cAMP sensitization group (n=5), and in the latter 3 groups, rat models of optic nerve injury models were established followed by intravitreal injection of PBS, 1716-OCM or cAMP as indicated. At 45 days after the treatments, the rats were examined for visual electrophysiological function using FVEP method, and the number of retinal ganglion cells (RGCs) and the expression of myelin basic protein in the optic nerve were detected using immunofluorescence assay. The recombinant 1716-OCM vector was capable of mediating effective expression of OCM in Vero cells in vitro, but its proliferation rate was much lower than that of the wild-type virus. In SD rats, the recombinant virus could mediate the expression of OCM in the RGC layer and choroid layer of the eyes without inducing significant structural damage of the eyes as compared with the wild-type virus. In rat models of optic nerve injury, 1716-OCM combined with cAMP significantly promoted the survival of retinal RGCs (P= 0.007) and inhibited demyelination of the optic nerve (P=0.03) as compared with the mock treatment. FVEP analysis showed that 1716-OCM combined with cAMP significantly promoted the recovery of the peak amplitude of ΔN1-P1 in the rats (P < 0.0001). Attenuated recombinant 1716-OCM vector can mediate OCM expression in the retina of rats, and in rat models of mechanical optic nerve injury, intravitreal injection of 1716-OCM combined with cAMP can effectively alleviate optic nerve injuries.

Amplitude Recovery and Deconvolution of Chirp and Boomer Data for Marine Geology and Offshore Engineering

The processing of Chirp data is limited by the usual recording of the signal envelope, which enhances its immediate visibility but prevents applying methods based on wave equations. This is normally not the case for Boomer data. However, both systems are monochannel instruments, which cannot estimate properly the propagation velocity of the signal in the rocks. In this paper, we present two theorems: the first one links the Chirp or Boomer source spectrum with an expected amplitude decay curve; the second one defines conditions for the deconvolution stability of the enveloped Boomer signal when the full waveform of the source signal is known. In this way, we can jointly process and integrate heterogeneous surveys including both data types. We validated the proposed algorithms by applying them to synthetic and real data. The presented tools can improve the image resolution and the characterization of geological formations in marine surveys by reflectivity anomalies, which are distorted by standard equalization methods.

Equalizer State Caching for Fast Data Recovery in Optically-Switched Data Center Networks

Optical switching offers the potential to significantly scale the capacity of data center networks (DCN) with a simultaneous reduction in switching time and power consumption. Previous research has shown that end-to-end switching time, which is the sum of the switch configuration time and the clock and data recovery (CDR) locking time, should be kept within a few nanoseconds for high network throughput. This challenge of low switching time has motivated research into fast optical switches, ultra-fast clock and amplitude recovery techniques. Concurrently, the data rate between server-to-server and server-to-switch interconnect is increasing drastically from the current 100 Gb/s (4 × 25 Gb/s) to 400 Gb/s and beyond, motivating the use of high order formats such as 50-GBaud four-level pulse-amplitude modulation (PAM-4) for signalling. Since PAM-4 is more sensitive to noise and distortion, digital equalizers are generally needed to compensate for impairments such as transceiver frequency roll-off, dispersion and optical filtering, adding additional time for equalizer adaptation and power consumption that are undesired for fast optical switching systems. Here we propose and investigate an equalizer state caching technique that reduces equalizer adaptation time and computation power consumption for fast optical switching systems, underpinning optically-switched DCNs using high baud rate and impairment-sensitive formats. Through a proof-of-concept experiment, we study the performance of the proposed equalizer state caching scheme in a three-node optical switching system using 56 GBaud PAM-4. Our experimental results show that the proposed scheme can tolerate up to ±0.8-nm (±100-GHz) instantaneous wavelength change with an adaptation delay of only 0.36 ns. Practical considerations such as clock phase misalignment, temperature-induced wavelength drift, and equalizer precision are also studied.

Local recovery of cardiac calcium-induced calcium release interrogated by ultra-effective, two-photon uncaging of calcium.

Key points In cardiac myocytes, subcellular local calcium release signals, calcium sparks, are recruited to form each cellular calcium transient and activate the contractile machinery.Abnormal timing of recovery of sparks after their termination may contribute to arrhythmias.We developed a method to interrogate recovery of calcium spark trigger probabilities and their amplitude over time using two‐photon photolysis of a new ultra‐effective caged calcium compound.The findings confirm the utility of the technique to define an elevated sensitivity of the calcium release mechanism in situ and to follow hastened recovery of spark trigger probabilities in a mouse model of an inherited cardiac arrhythmia, which was used for validation.Analogous methods are likely to be applicable to investigate other microscopic subcellular signalling systems in a variety of cell types. In cardiac myocytes Ca2+‐induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) through ryanodine receptors (RyRs) governs activation of contraction. Ca2+ release occurs via subcellular Ca2+ signalling events, Ca2+ sparks. Local recovery of Ca2+ release depends on both SR refilling and restoration of Ca2+ sensitivity of the RyRs. We used two‐photon (2P) photolysis of the ultra‐effective caged Ca2+ compound BIST‐2EGTA and laser‐scanning confocal Ca2+ imaging to probe refractoriness of local Ca2+ release in control conditions and in the presence of cAMP or low‐dose caffeine (to stimulate CICR) or cyclopiazonic acid (CPA; to slow SR refilling). Permeabilized cardiomyocytes were loaded with BIST‐2EGTA and rhod‐2. Pairs of short 2P photolytic pulses (1 ms, 810 nm) were applied with different intervals to test Ca2+ release amplitude recovery and trigger probability for the second spark in a pair. Photolytic and biological events were distinguished by classification with a self‐learning support vector machine (SVM) algorithm. In permeabilized myocytes data recorded in the presence of CPA showed a lower probability of triggering a second spark compared to control or cAMP conditions. Cardiomyocytes from a mouse model harbouring the arrhythmogenic RyRR420Q mutation were used for further validation and revealed a higher Ca2+ sensitivity of CICR. This new 2P approach provides composite information of Ca2+ release amplitude and trigger probability recovery reflecting both SR refilling and restoration of CICR and RyR Ca2+ sensitivity. It can be used to measure the kinetics of local CICR recovery, alterations of which may be related to premature heart beats and arrhythmias.

Oxytocin Receptor Activation Rescues Opioid-Induced Respiratory Depression by Systemic Fentanyl in the Rat.

Opioid overdose intervention by naloxone, a high affinity receptor antagonist, reverses opioid-induced respiratory depression (OIRD) and analgesia by displacing opioids. Systemic naloxone stimulates release of the hypothalamic neuropeptide oxytocin, which has analgesic properties and participates in cardiorespiratory homeostasis. To test the hypothesis that oxytocin can reverse OIRD, we assessed the rescue potential of graded doses (0, 0.1, 2, 5, 10, 50 nmol/kg, i.v.) of oxytocin to counter fentanyl (60 nmol/kg, i.v.)-induced depression of neural inspiration indexed by recording phrenic nerve activity (PNA) in anesthetized (urethane/α-chloralose), vagotomized, and artificially ventilated rats. Oxytocin dose-dependently rescued fentanyl OIRD by almost immediately reversing PNA burst arrest (P = 0.0057) and restoring baseline burst frequency (P = 0.0016) and amplitude (P = 0.0025) at low but not high doses, resulting in inverted bell-shaped dose-response curves. Oxytocin receptor antagonism (40 nmol/kg, i.v.) prevented oxytocin reversal of OIRD (arrest: P = 0.0066, frequency: P = 0.0207, amplitude: P = 0.0022). Vasopressin 1A receptor (V1aR) antagonism restored high-dose oxytocin efficacy to rescue OIRD (P = 0.0170 to P < 0.0001), resulting in classic sigmoidal dose-response curves, and prevented (P = 0.0135) transient hypertension from V1aR cross-activation (P = 0.0275). Alone, vasopressin (5 nmol/kg, i.v.) failed to reverse fentanyl respiratory arrest (P = 0.6184). The nonpeptide oxytocin receptor agonist WAY-267464 (75 nmol/kg, i.v.), which has V1aR antagonist properties, quickly reversed fentanyl OIRD (P < 0.0001), with rapid recovery of PNA frequency (P = 0.0011) and amplitude (P = 0.0044) without adverse hemodynamic consequences (P = 0.9991). Findings indicate that peptide and nonpeptide agonist activation of oxytocin receptors without V1aR cross-activation rescues fentanyl OIRD. Oxytocin receptor agonists could be lifesaving resuscitation agents that enhance rather than interrupt opioid analgesia. SIGNIFICANCE STATEMENT: Oxytocin receptor activation produces analgesia. Here, we demonstrate that activation by the US Food and Drug Administration-approved agonist oxytocin and the nonpeptide partial agonist WAY-267464 can each reverse fentanyl cardiorespiratory depression. Selective targeting of oxytocin receptors for resuscitation from opioid overdose, alone or in combination with an opioid antagonist, could eliminate or attenuate negative side effects associated with traditional opioid receptor antagonism.

Quantifying the data quality of focal series for inline electron holography

Inline electron holography, the recovery of amplitude and phase of an electron wave function having passed through a thin specimen from a focal series recorded in a transmission electron microscope is being applied in many labs worldwide. At medium range magnification (i.e. typically ≥0.8 nm where the lattice of small unit cell crystals such as silicon is not resolved), where the defocus needs to be varied over a rather large range of several hundred nm or even μm, the retrieval of low spatial frequency information is severely affected by the choice of experimental parameters as well as the way of data normalization. Methods to quantitatively analyze the reliability of phase maps obtained by inline electron holography are presented, and data recorded and processed in different ways are compared. While, even under optimized conditions, the phase reconstructed from an experimental focal series still lacks very low spatial frequency components, regularization schemes exist and are demonstrated to effectively hide artifacts associated with this lack of information.

Portable Diagnostic System for Age-Related Macular Degeneration Screening Using Visual Evoked Potentials.

BackgroundDelayed Dark-Adapted vision Recovery (DAR) is a biomarker for Age-related Macular Degeneration (AMD), however its measurement is burdensome for patients and examiners.MethodsIn this study, we developed a portable, wireless and user-friendly system that employs a headset with a smartphone to deliver controlled photo-bleach and monocular pattern reversal stimuli, while using custom electroencephalography (EEG) electrodes and electronics in order to measure Dark-Adapted Visual Evoked Potentials (DAVEP) objectively and separately at the peripheral and central visual field. This is achieved in one comfortable 20-minute session, without requiring subject reporting. DAVEP responses post photo-bleach for up to 15 minutes were measured concurrently from both eyes in 12 AMD-patients, 1 degenerative myopia patient, and 8 controls who had no diagnosed macular vision loss.ResultsRobust positive polarity DAVEP responses were observed at 200–500 ms from stimulus onset to scotopic stimuli that have been seldom reported and analyzed previously. The amplitude recovery of the DAVEP response was significantly delayed in AMD patients as compared to controls. We developed DAVEP1 scores, a simple metric for DAR, which classified 90% of subject eyes correctly, indicating the presence of AMD in at least one eye of all pre-confirmed subjects with this diagnosis.ConclusionWe developed a user-friendly, portable VEP system and DAVEP1 metric, which show a high potential to identify DAR-deficits in AMD-patients. This novel technology could aid in early diagnosis of AMD.

Methods of antenna and «antenna- radome» system analysis based on amplitude and phase measurements of their far field spherical components

The main principles of electric intensity recovery of electrical field in tested antenna aperture or in the «antenna radome» system radome-close aperture field (false aperture) by amplitude and phase long-range measurements are proposed. Measurements zone means a part of the spherical surface that envelopes analyzed antenna, the boarder of this surface are determined by the kinematic scheme of rotary joint of the scanner. Recovery of amplitude and phase distribution of the field in a flat aperture area or on the plane where array irradiators are located is used in case of wave diagnostics of such type of antennas. It is proposed to use the recovered phase distribution in a false aperture for a phase correction on phased array irradiators in order to compensate phase errors appeared because of the radome. The method of radome dielectric permittivity is discussed.

Robust Power Sharing and Voltage Stabilization Control Structure via Sliding-Mode Technique in Islanded Micro-Grid

With a focus on the problems of active power sharing and voltage deviation of parallel-connected inverters in an islanded micro-grid (MG), in this study, the power-voltage droop controller and the inner voltage regulator are redesigned based on a total sliding-mode control (TSMC) technique. As for the power-voltage droop control loop, a droop control relation error between the active power and the point-of-common-coupling (PCC) voltage amplitude is defined. Then, the TSMC scheme is adopted to reach the new droop control relation, where the active power sharing and voltage amplitude recovery can be achieved simultaneously. Owing to the faster dynamic response and strong robustness provided by the TSMC framework, high-precision active power sharing during transient state also can be ensured without the influence of line impedances. The power allocation error can be improved by more than 81.2% and 50% than the conventional and proportional-integral (PI)-based droop control methods, respectively, and the voltage deviation rate can be reduced to 0.16%. Moreover, a small-signal model of the TSMC-based droop-controlled system is established, and the influences of control parameters on the system stability and the dynamic response are also investigated. The effectiveness of the proposed control method is verified by numerical simulations and experimental results.

An antibody to RGMa promotes regeneration of cochlear synapses after noise exposure

Auditory neuropathy is caused by the loss of afferent input to the brainstem via the components of the neural pathway comprising inner hair cells and the first order neurons of the spiral ganglion. Recent work has identified the synapse between cochlear primary afferent neurons and sensory hair cells as a particularly vulnerable component of this pathway. Loss of these synapses due to noise exposure or aging results in the pathology identified as hidden hearing loss, an initial stage of cochlear dysfunction that goes undetected in standard hearing tests. We show here that repulsive axonal guidance molecule a (RGMa) acts to prevent regrowth and synaptogenesis of peripheral auditory nerve fibers with inner hair cells. Treatment of noise-exposed animals with an anti-RGMa blocking antibody regenerated inner hair cell synapses and resulted in recovery of wave-I amplitude of the auditory brainstem response, indicating effective reversal of synaptopathy.

Sparsity‐promoting least‐squares reverse time migration via preconditioned Bregmanized operator splitting

ABSTRACTNowadays the least‐squares reverse time migration has become the most used migration method because of its accuracy in amplitude recovery and high‐resolution imaging, specifically its priority to image the beneath of structural domes such as salt domes. However, errors in the migration velocity model, inadequate physics of modelling/migration and too sparse data decrease the quality of the migrated image. Sparsity constraints help to mitigate the shortcomings of the least‐squares reverse time migration and stabilize the migration image, but the computational burden of sparse solvers is still a big challenge. In this paper, we propose a fast sparsity‐promoting least‐squares reverse time migration algorithm based on the Bregmanized operator splitting algorithm. In particular, we solve the least‐squares reverse time migration with ‐norm regularization to increase the image resolution while removing the artefacts which cannot be suppressed by the traditional least‐squares reverse time migration. Also we develop a preconditioned Bregmanized operator splitting algorithm where iteratively using of a preconditioner decreases the computational burden. The proposed method is applied to a few sets of synthetic data, and results are compared with reverse time migration or least‐squares reverse time migration to verify its superiority. Numerical tests demonstrate that the proposed preconditioned Bregmanized operator splitting algorithm converges to the desired migration image in a small number of iterations.

Alleviation of extensive visual pathway dysfunction by a remyelinating drug in a chronic mouse model of multiple sclerosis.

Visual deficits are among the most prevalent symptoms in patients with multiple sclerosis (MS). To understand deficits in the visual pathway during MS and potential treatment effects, we used experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The afferent visual pathway was assessed in vivo using optical coherence tomography (OCT), electroretinography (ERG), and visually evoked cortical potentials (VEPs). Inflammation, demyelination, and neurodegeneration were examined by immunohistochemistry ex vivo. In addition, an immunomodulatory, remyelinating agent, the estrogen receptor β ligand chloroindazole (IndCl), was tested for its therapeutic potential in the visual pathway. EAE produced functional deficits in visual system electrophysiology, including suppression of ERG and VEP waveform amplitudes and increased signal latencies. Therapeutic IndCl rescued overall visual system latency by VEP but had little impact on amplitude or ERG findings relative to vehicle. Faster VEP conduction in IndCl‐treated mice was associated with enhanced myelin basic protein signal in all visual system structures examined. IndCl preserved retinal ganglion cells (RGCs) and oligodendrocyte density in the prechiasmatic white matter, but similar retinal nerve fiber layer thinning by OCT was noted in vehicle and IndCl‐treated mice. Although IndCl differentially attenuated leukocyte and astrocyte staining signal throughout the structures analyzed, axolemmal varicosities were observed in all visual fiber tracts of mice with EAE irrespective of treatment, suggesting impaired axonal energy homeostasis. These data support incomplete functional recovery of VEP amplitude with IndCl, as fiber tracts displayed persistent axon pathology despite remyelination‐induced decreases in latencies, evidenced by reduced optic nerve g‐ratio in IndCl‐treated mice. Although additional studies are required, these findings demonstrate the dynamics of visual pathway dysfunction and disability during EAE, along with the importance of early treatment to mitigate EAE‐induced axon damage.

Neurophysiological Changes in the First Year After Cell Transplantation in Sub-acute Complete Paraplegia.

Neurophysiological testing can provide quantitative information about motor, sensory, and autonomic system connectivity following spinal cord injury (SCI). The clinical examination may be insufficiently sensitive and specific to reveal evolving changes in neural circuits after severe injury. Neurophysiologic data may provide otherwise imperceptible circuit information that has rarely been acquired in biologics clinical trials in SCI. We reported a Phase 1 study of autologous purified Schwann cell suspension transplantation into the injury epicenter of participants with complete subacute thoracic SCI, observing no clinical improvements. Here, we report longitudinal electrophysiological assessments conducted during the trial. Six participants underwent neurophysiology screening pre-transplantation with three post-transplantation neurophysiological assessments, focused on the thoracoabdominal region and lower limbs, including MEPs, SSEPs, voluntarily triggered EMG, and changes in GSR. We found several notable signals not detectable by clinical exam. In all six participants, thoracoabdominal motor connectivity was detected below the clinically assigned neurological level defined by sensory preservation. Additionally, small voluntary activations of leg and foot muscles or positive lower extremity MEPs were detected in all participants. Voluntary EMG was most sensitive to detect leg motor function. The recorded MEP amplitudes and latencies indicated a more caudal thoracic level above which amplitude recovery over time was observed. In contrast, further below, amplitudes showed less improvement, and latencies were increased. Intercostal spasms observed with EMG may also indicate this thoracic “motor level.” Galvanic skin testing revealed autonomic dysfunction in the hands above the injury levels. As an open-label study, we can establish no clear link between these observations and cell transplantation. This neurophysiological characterization may be of value to detect therapeutic effects in future controlled studies.

Photoelectric dye-based retinal prosthesis (OUReP) as a novel type of artificial retina

We have developed the world's first novel type of artificial retina, OUReP (Okayama University Retinal Prosthesis), in which a photoelectric dye that converts light energy into electric potential is covalently bonded to the surface of a polyethylene thin film as an insulator. The receptor that absorbs light and the output device that generates displacement current to stimulate nearby neurons are integrated in a sheet of thin film. It has become possible to measure the surface potential of the artificial retina OUReP using a Kelvin probe that measures the surface potential of semiconductors. When light is turned on and off to the artificial retina OUReP, the surface potential changes rapidly. As the light intensity is increased, the potential change on the surface of the artificial retina becomes larger. As for safety, the artificial retina OUReP was not toxic in all tests for biological evaluation of medical devices. As for efficacy, the artificial retina OUReP was implanted under the retina by vitreous surgery in monkey eyes which had chemically-induced macular degeneration with photoreceptor cell loss. Over the next 6 months, retinal detachment did not occur during the course, and the artificial retina was in contact with the retinal tissue. The amplitude of the visual evoked potential attenuated by macular degeneration recovered 1 month after implantation of the artificial retina, and the recovery of amplitude was maintained until 6 months after the implantation. By using multielectrode array-mounted dish recording system, it has been proved that action potential spikes are induced when the artificial retina is placed on degenerative retinal tissue of retinal dystrophic rats or mice and exposed to light, which is used as an index of the effectiveness of the artificial retina. We have established manufacturing and quality control of the device in a clean room facility, proved the safety and efficacy, and are preparing for first-in-human investigator-initiated clinical trials.

Attacking asymmetric cryptosystem based on phase truncated Fourier fransform by deep learning

Most of optical encryption systems are symmetric cryptosystems. The plaintext and the ciphertext in optical image encryption are related linearly. The security of the system needs to be strengthened. The asymmetric cryptosystem based on phase truncated Fourier transforms (PTFT) makes the security of the encryption system greatly improved by its nonlinear phase truncation. Deep learning (DL) as a method of machine learning was proposed decades ago. With the development of computer’s performance, the practicality of deep learning proves to be more and more obvious. Recently, deep learning has been effectively used in many fields such as biomedicine, object detection, etc. The good results have been achieved. In this article proposed is the attack to the PTFT encryption system by deep learning. Through the PTFT encryption system, we construct a plaintext-ciphertext paired image dataset and then train it by residual network (ResNet). There are two problems encountered by the traditional neural network model. One is vanishing or named exploding gradient, which makes training effect difficult to converge and the other is a degradation phenomenon. When continuing to increase the number of layers for a suitable depth model, the model accuracy will decline which is not caused by overfitting. This problem can be solved by the ResNet to a certain extent by directly bypassing and then taking the input information to the output to protect the integrity of the information. The biggest difference between ordinary directly connected convolutional neural networks and ResNet is that the ResNet has many bypass branches that directly connect the input to the subsequent layers, so that the subsequent layers can directly learn the residuals. The ResNet can automatically learn the decryption characteristics of the encryption system. Finally, the test set is used to test the decryption performance of the trained model. The data show that the model can restore the image with high quality and the model has a certain anti-noise ability. Compared with the two-step iterative amplitude recovery algorithm, the the method proposed in this paper can recover high quality image.

Epigraphical Relaxation for Minimizing Layered Mixed Norms

This paper proposes an epigraphical relaxation (ERx) technique for non-proximable mixed norm minimization. Mixed norm regularization methods play a central role in signal reconstruction and processing, where their optimization relies on the fact that the proximity operators of the mixed norms can be computed efficiently. To bring out the power of regularization, sophisticated layered modeling of mixed norms that can capture inherent signal structure is a key ingredient, but the proximity operator of such a mixed norm is often unavailable (non-proximable). Our ERx decouples a layered non-proximable mixed norm into a norm and multiple epigraphical constraints. This enables us to handle a wide range of non-proximable mixed norms in optimization, as long as both the proximal operator of the outermost norm and the projection onto each epigraphical constraint are efficiently computable. Moreover, under mild conditions, we prove that ERx does not change the minimizer of the original problem despite relaxing equality constraints into inequality ones. We also develop new regularizers based on ERx: one is decorrelated structure-tensor total variation for color image restoration, and the other is amplitude-spectrum nuclear norm for low-rank amplitude recovery. We examine the power of these regularizers through experiments, which illustrates the utility of ERx.

Combining reverse end-to-side neurorrhaphy with rapamycin treatment on chronically denervated muscle in rats

This preliminary research determines whether a combination of reverse end-to-side neurorrhaphy and rapamycin treatment achieves a better functional outcome than a single application after prolonged peripheral nerve injury. We found that the tibial nerve function of the reverse end-to-side + rapamycin group recovered better, with a higher tibial function index value, higher amplitude recovery rate, and shorter latency delay rate (P < 0.05). The reverse end-to-side + rapamycin group better protected the gastrocnemius muscle with more forceful contractility, tetanic tension, and a higher myofibril cross-sectional area (P < 0.05). Combining reverse end-to-side neurorrhaphy with rapamycin treatment is a practical approach to promoting the recovery of chronically denervated muscle atrophy after peripheral nerve injury.

Hyperglycemia regulates cardiac K+ channels via O-GlcNAc-CaMKII and NOX2-ROS-PKC pathways.

Chronic hyperglycemia and diabetes lead to impaired cardiac repolarization, K+ channel remodeling and increased arrhythmia risk. However, the exact signaling mechanism by which diabetic hyperglycemia regulates cardiac K+ channels remains elusive. Here, we show that acute hyperglycemia increases inward rectifier K+ current (IK1), but reduces the amplitude and inactivation recovery time of the transient outward K+ current (Ito) in mouse, rat, and rabbit myocytes. These changes were all critically dependent on intracellular O-GlcNAcylation. Additionally, IK1 amplitude and Ito recovery effects (but not Ito amplitude) were prevented by the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor autocamtide-2-related inhibitory peptide, CaMKIIδ-knockout, and O-GlcNAc-resistant CaMKIIδ-S280A knock-in. Ito reduction was prevented by inhibition of protein kinase C (PKC) and NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). In mouse models of chronic diabetes (streptozotocin, db/db, and high-fat diet), heart failure, and CaMKIIδ overexpression, both Ito and IK1 were reduced in line with the downregulated K+ channel expression. However, IK1 downregulation in diabetes was markedly attenuated in CaMKIIδ-S280A. We conclude that acute hyperglycemia enhances IK1 and Ito recovery via CaMKIIδ-S280 O-GlcNAcylation, but reduces Ito amplitude via a NOX2-ROS-PKC pathway. Moreover, chronic hyperglycemia during diabetes and CaMKII activation downregulate K+ channel expression and function, which may further increase arrhythmia susceptibility.

Randomised study evaluating the pharmacodynamics of emixustat hydrochloride in subjects with macular atrophy secondary to Stargardt disease

Background/AimsStargardt disease is a rare, inherited, degenerative disease of the retina that is the most common type of hereditary macular dystrophy. Currently, no approved treatments for the disease exist. The...

Abstract 113: Effects of Anticoagulation and Thrombolytic Therapy in a Porcine Model of Prolonged Out-of-hospital Cardiac Arrest Treated with ECPR

Background: Extracorporeal cardiopulmonary resuscitation (ECPR) has been used in patients with refractory out-of-hospital cardiac arrest (OHCA). However, recovery of organ function and survival are potentially impaired due to microvascular coagulation causing a “no-reflow” phenomenon. Hypothesis: Early anticoagulant therapy (argatroban) during CPR and/or thrombolytic therapy (streptokinase) at ECPR onset improves recovery of organ function in an OHCA porcine model. Methods: In a blinded and randomized study, 48 swine (40±5kg) were subjected to 8min of ventricular fibrillation cardiac arrest (CA) followed by 30min of goal directed CPR (gdCPR), and 8h of ECPR (33°C) with heparin anticoagulation during ECPR. Animals (n=12) were randomized to one of 4 groups with 350mg/kg argatroban (Arg) or placebo (20mL NSS) given 12min after CA onset and 1.5 MU streptokinase (STK) or placebo (50mL NSS) given at ECPR initiation: Group 1 (placebo and placebo); Group 2 (Arg and placebo); Group 3 (placebo and STK); and Group 4 (Arg and STK). Recovery of cardiac function measured by a cardiac resuscitablity score (CRS), see Table. Recovery of neurologic function measured by amplitude recovery of cortical somatosensory evoked potentials (cSSEP). Data analysis: Kruskal Wallis and single factor ANOVA tests with ( p &lt;0.05 significant). Results: Average CRS and cSSEP recovery were not significantly different between groups. However, the combined average CRS of the argatroban groups (2&amp;4) was 3.2±2.1 compared to 2.0±1.6 for the groups without it (1&amp;3), p =0.03 single factor ANOVA. Furthermore, more animals in groups 2&amp;4 (n=8) achieved a robust recovery in cSSEP amplitude (≥30% amplitude return) than in groups 1&amp;3 (n=4). Discussion: These results provide evidence that argatroban given early during CPR potentially improves early recovery of cardiac and neurological function in a porcine model of OHCA. However, the impact of these therapies on long term recovery remains to be determined.