Potential Duration Research Articles

Clinical significance of D4A in prostate cancer therapy with abiraterone

Androgen deprivation therapy (ADT), either by surgical or medical castration depletes testicular production of testosterone (T) and has long been considered as the mainstay of upfront treatment for advanced prostate cancer. Despite the initial response to this treatment, disease progression to castration-resistant prostate cancer (CRPC) usually occurs. The adrenal production of androgen precursor steroids, such as dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S), permits intratumoral production of T and 5α-dihydrotestosterone (DHT), activation of androgen receptor (AR) and AR-dependent gene expression. Abiraterone (Abi; given as Abi acetate) and enzalutamide (Enz) are 2 of the agents that target different parts of the androgen pathway by blocking androgen production and signaling, ultimately improving overall survival for patients with metastatic CRPC.1,2 Abi is a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), which is a key enzyme required for DHEA and DHEA-S production. Synthesis of DHT, the most potent androgen, from DHEA necessitates a series of enzymes, including 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A), and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. This process enables the conversion of ADT-responsive prostate cancer into CRPC. Multiple retrospective reviews have shown the limited efficacy of Enz after Abi treatment failure and vice versa.3,4 To date there are very little data on the appropriate sequence of Enz and Abi utilization, which might thereby maximize the potential efficacy and duration of response to treatment with these agents. Our recently published research demonstrates that Δ4, 3-keto-abi (D4A) is a metabolite of Abi that is formed in patients with prostate cancer and has CYP17A1 inhibition activity that is comparable to Abi.5 Furthermore, D4A inhibits 3βHSD (a key enzyme involved in CRPC progression) more potently than Abi and at higher concentrations it demonstrates significant SRD5A inhibitory effects as well. Moreover, although Abi has been shown to have AR antagonistic activity,6 we observed more potent AR inhibition activity with D4A that is comparable to Enz in our experiments.5 As a result, by targeting multiple steps of the AR signaling pathway, D4A showed a significant increase in progression free survival compared to Abi and Enz in our xenograft models, suggesting that it might play an important role in the clinical activity of Abi in CRPC patients. Abi is converted to D4A by 3βHSD. Increased 3βHSD enzymatic function, with the HSD3B1(1245C) genetic variant encoding a missense in 3βHSD1 as one known mechanism, also increases intratumoral flux to DHT that may result in the development of treatment resistance.7 Therefore, D4A conversion ratio could serve as an indicator of 3βHSD activity and ultimately may predict resistance to hormonal therapy for prostate cancer. On the other hand, higher 3βHSD activity would translate into a higher D4A concentration, which is a more potent metabolite than Abi as described above. Although the Abi to D4A conversion ratio is low (at about 5%) in most patients, it appears to be quite variable. A higher conversion ratio might mimic conditions of treatment with Enz, particularly given the AR antagonist activity of D4A. In other words, 3βHSD activity level in a patient might be helpful in predicting the potential response to Abi and ultimately a patient with higher concentration of D4A with Abi treatment might be less likely to benefit from subsequent Enz treatment. Conversely, increasing D4A levels by increasing Abi concentrations or the conversion to D4A might increase the clinical benefit of treatment with Abi. In addition, because 3βHSD is required for mineralocorticoid synthesis, 3βHSD inhibition by D4A might reduce mineralocorticoid production that could translate into a better side effect profile (less hypertension and hypokalemia) and potentially lower dose of prednisone requirement in patients with higher D4A levels. These questions have yet to be answered in clinical studies. Finally, it is possible that steroidogenic metabolites of Abi are not limited to D4A, and that other metabolites with clinically relevant biochemical activity contribute to response and resistance to treatment with Abi.

Electrophysiological, haemodynamic, and mitochondrial alterations induced by levobupivacaine during myocardial ischemia in a pig model: protection by lipid emulsions?

Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid(®) ), (iii) levobupivacaine, (iv) combination levobupivacaine-Intralipid(®) . Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax ). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/dtmax . At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid(®) quickly improved haemodynamics. However, beneficial effects of Intralipid(®) were less clear after myocardial ischemia.

Abstract 362: Cardioprotective Effects of Adiponectin in Volume Overload Induced Electrophysiological Remodeling

The electrophysiological hallmark of the failing heart is the prolongation of action potential duration that induces arrhythmia and sudden death. Depressed outward potassium currents (Ito) has been implicated as the major cause of altered action potential during ventricular remodeling. The molecular mechanism underlying depressed Ito in the diseased heart is still poorly understood. Recent studies have demonstrated that adiponectin (APN) has a cardio-protective effect in response to various pathological stimuli; however, little information is available regarding the potential effects of APN on electrophysiological remodeling under pathological conditions. The present study were to determine the effect of adiponectin treatment on ventricular potassium channel function in a rat model of volume overload induced heart failure. Volume-overload was induced by surgical creation of an infrarenal aorta-vena cava fistula. Rats were administrated with or without adenovirus-mediated overexpression of adiponectin (Ad-APN) at 2-, 5- and 8- weeks post-fistula. In vivo ECGs were used to evaluate changes in QT interval in rats at 10 weeks post-fistula. Ventricular myocytes were isolated at 10 weeks post-fistula. Western blots were used to measure cytoplasmic and membrane protein expression of potassium channels Kv4.2 and Kv 4.3, as well as, KChIP2. Whole cell patch clamp was used to evaluate action potential and Ito currents. Results showed that adiponectin levels in serum and myocytes were significantly reduced following fistula. The duration of action potential was prolonged in ventricular myocytes following 10-week fistula, which was correlated with the in vivo QT interval prolongation, as well as a depression of functional Ito and decreased protein expression of Ito channel subunits in ventricular myocytes. In vivo supplementation of Ad-APN increased the protein levels of Ito channel subunits and prevented Ito depression in ventricular myocytes following 10-week fistula. This further restored the duration of action potential and the QT interval on the ECG back to the normal. These results indicate that adiponectin was able to prevent volume overload-induced ventricular electrophysiological remodeling.

Electrophysiological change in the tensor veli palatini muscle after radiotherapy

Conclusion: Electromyography of the tensor veli palatine (TVP) was abnormal and showed mainly myogenic impairment in patients with nasopharyngeal carcinoma (NPC) with secretory otitis media (SOM) after radiotherapy. The diseased ears showed impairment in opening functions of the eustachian tubes (ETs). Objectives: To characterize electrophysiology of the TVP muscle using electromyography (EMG) in patients with SOM after radiotherapy of NPC. Methods: Twenty healthy volunteers and 20 patients with NPC and SOM after radiotherapy were chosen for assessment of EMG of the TVP during swallowing. Results: The measurements of average duration and amplitude of action potential, swallowing contraction duration, and peak voltage in NPC patients with both SOM (n = 25) and healthy ears (n = 6) were significantly lower than those of ears (n = 38) in healthy controls (p < 0.01). In patients with NPC, the average action potential duration and swallowing contraction duration in ears with SOM were lower than those of subjects with healthy ears (p < 0.05), whereas no significant difference was found in average amplitude of action potential and peak voltage between them.

Modified ligation of the intersphincteric fistula tract in the treatment of simple transsphincteric perianal fistula

To assess the efficacy and safety of modified ligation of the intersphincteric fistula tract for simple transsphincteric perianal fistula. Seventy patients with simple transsphincteric perianal fistula between October 2012 and January 2014 in our department were prospectively enrolled. According to the random number table, patients were divided into two groups: modified-LIFT group (37 cases, from the external opening close to the fistula, dissect the external sphincter fistula to the intersphincteric groove by tunneling technique, resect the lateral free fistula) and LIFT group (33 cases). Clinical parametres before and after operation were compared, and results of pelvic electromyogram (EMG) and anorectal manometry three months after operation were analyzed to evaluated anal function. The operative time, pain score, hospital stay, and healing time were not significantly different between the two groups (all P>0.05). During the median follow-up of 12 months (3-20 months), the healing rate in modified-LIFT group was 83.8% (31/37), which was significantly higher than 60% (20/33) in LIFT group (P=0.029). After operation, 4 patients had persistent unhealed wound, 2 recurred in modified-LIFT group, while 8 patients had persistent unhealed wound, and 5 recurred in LIFT group. No patients developed anal incontinence. By the pelvic EMG and anorectal manometry 3 months after operation, the duration of motor unit potential, occurrence of simple phase, mean resting pressure and maximun squeeze pressure were not significantly different. Modified-LIFT procedure for the management of simple transsphincteric perianal fistulas is a simple and effective operation with higher healing rate and similar anal function as LIFT.

Abstract 17272: Ionic Current Remodeling Delays the Electrical Recovery of the Senescent Heart

Cardiac aging is associated with lengthening of the QT interval, a condition that enhances malignant ventricular arrhythmias and sudden death. The aim of this study was to establish whether ionic currents are altered in old myocytes contributing to the protracted electrical recovery of the senescent heart. Thus, mice at 3-30 months of age were studied by ECG and patch-clamp; these physiological determinations were complemented with molecular assays for the analysis of ion channel proteins. By surface ECG and telemetry system, PR, QRS and QT intervals were prolonged in mice at 25 months or older. These delays were maintained in ex-vivo Langendorff preparations. In comparison to young, epicardial monophasic action potential (AP) duration at 50% and 90% repolarization were 1.6- and 1.2-fold larger in old LV, respectively. Moreover, senescent hearts presented a 60% higher incidence of arrhythmias. In isolated myocytes, prolongation of the early (+47%), intermediate (+117%) and late (+75%) repolarization phases of the AP were identified in cells from old animals, whereas resting membrane potential, upstroke amplitude and +dV/dt were preserved. Voltage-clamp experiments were then performed to measure ionic current properties. The rapidly activating K+ current, which consists of the transient outward and ultrarapid delayed rectifier (Ito+Kur), is responsible for the early repolarization of the AP, and was significantly reduced in old myocytes. Molecular studies revealed low levels of transcripts and proteins for K+ channel subunits Kv1.4, Kv1.5 and KChiP2 in senescent cells. Also, the late Na+ current INaL, which presents slow inactivation kinetics and is operative during AP repolarization, was 1.5-fold larger in old cells. These changes were associated with alterations in gene and protein expression of Na+ channel subunits. Inhibition of INaL with mexiletine significantly shortened the intermediate and late repolarization phases of the AP in both myocytes and perfused myocardium from old mice. Importantly, INaL inhibition in vivo shortened the QT interval of senescent mice by 12%. Thus, defects in ionic current occur with aging resulting in prolongation of the AP and delays in electrical recovery which may lead to malignant ventricular arrhythmias.

Aqueous and salt solutions of quinine of low concentrations: Self-organization, physicochemical properties and actions on the electrical characteristics of neurons

Self-organization, the physicochemical properties of aqueous and salt solutions of quinine and the effects of salt quinine solutions in a wide range of concentrations (1 x 10(-22) - 1 x 10(-3) M) on the electrical characteristics of the edible snail's identified neurons were studied. Similar non-monotonic concentration dependencies of physicochemical properties of aqueous and salt quinine solutions at low concentrations are obtained. This allows of predicting the occurrence of biological effects at low concentrations of quinine solutions. Intrinsic (within 5% of the interval) changes in membrane potential, the amplitude and duration of the neuron action potential under the influence of quinine salt solutions at concentrations of quinine of 1 x 10(-20), 1 x 10(-18), 1 x 10(-10) M are found. For these concentrations the extreme values of specific conductivity and pH are shown.

Effects of interleukin-18 on bioelectric activity of rat atrial cardiomyocytes under normal conditions and during gradual stretching of the tissue.

Effects of IL-18 (50 ng/ml) on bioelectric activity of rat atrial cardiomyocytes under normal conditions and after gradual stretching of the tissue was studied using microelectrode technique. It was shown that in 85% experiments, IL-18 increased the duration of action potential at the level of 25, 50, and 90% repolarization without changing the magnitude of the resting potential, amplitude and repetition rate of action potentials, and cardiomyocyte contraction force. In addition, IL-18 abolished mechanically induced changes in the shape of action potentials during stretching.

Chevron Position Qualification System for Development of Emergency Response Leadership

ABSTRACT The 2010 Deepwater Horizon incident raised the awareness of the potential scale, complexity and duration of oil spill events, highlighting the need for emergency response organizations to develop and maintain advanced levels of capability and readiness. Such capability and readiness requires teams of experienced and trained personnel who ideally can be cascaded throughout an enterprise to fill Incident Command System (ICS) positions in coordination with outside organizations. Experience gained through either responses to real- world events or carefully crafted simulation exercises is critical to the development and maintenance of response team capability, and providing such can present a significant challenge for team coordinators. Chevron Corporate Emergency Response developed and tested a qualification program aimed at providing consistency and structure to the training and experiential development of Chevron's corporate emergency response personnel. The Chevron Position Qualification System (CPQS) program establishes a minimum level of training and observed demonstrated competencies for leadership positions within the ICS structure. Twenty-one position-specific workbooks detail training, readiness and competency metrics for internal certification through the program. CPQS draws from different established agency programs and is consistent with ICS training curriculum. The program is tailored to fit the roles filled by Chevron Corporate Emergency Response Team members. Members of Chevron's Corporate Emergency Response Teams have a baseline of professional training that supports and sustains a corporate culture of safety, operational discipline and environmental, safety risk and hazard awareness. The CPQS program was built upon the premise that participants have this foundational training, capability and professionalism. The CPQS program builds upon this foundation, expanding the professional competency of response personnel through a standardized program. The CPQS program establishes minimum ICS and function-specific courses along with recommended training and the demonstration of specified skills and abilities in either real-world or exercise environments. Qualified and vetted approvers, known within the program a Qualified Approvers, provide consistent verification of the demonstration of skills and capabilities identified for each position. Additionally, these expert observers provide commentary on areas where skills or professional expertise can be improved. The goal of CPQS is to enable a mobile and versatile workforce that can respond worldwide and integrate into response organizations around the globe. Skills gained through the completion of CPQS requirements enable business units to transfer personnel into key response positions across the enterprise to carry out responses to more complex events. Common training and exercising goals allow organizations to gain efficiencies and build progressive experience and expertise-building opportunities through shared professional development resources. Periodic refresher training and ongoing participation in response exercises or actual incidents are also required to maintain the certification. The CPQS program is currently used by Chevron's Corporate Emergency Response Teams and was field tested at a three-day response exercise in Trieste, Italy where responders from relevant functional groups completed training and demonstrated response capabilities and ICS skills. CPQS is also being utilized with the Chevron regional response team in the Gulf of Mexico with an initial implementation at a training and exercise event in Covington, Louisiana, USA.

Measuring brain temperature without a thermometer.

Temperature has profound effects on a wide range of parameters of neural activity at various scales (Hodgkin and Katz, 1949). At the cell level, ionic currents, membrane potential, input resistance, action potential amplitude, duration and propagation, and synaptic transmission have all been shown to be affected by temperature variations (Hodgkin and Katz, 1949; Kullmann and Asztely, 1998; Volgushev et al., 2000a,b; Fujii et al., 2002). At mesoscopic scales of neural activity, temperature changes can steer network activity toward different functional regimes (Reig et al., 2010), affecting the duration, frequency and firing rate of activated states during slow frequency oscillations, and the ability to end these states (Compte et al., 2003). Temperature also has a substantial effect on chemical reaction rates (Swan, 1974), and affects the blood oxygen saturation level by changing haemoglobin affinity for oxygen (Guyton, 1987). Furthermore, cooling reduces metabolic processes (Esmann and Skou, 1988), and has been used to silence cortical areas to study their function (Uyeda and Fuster, 1967). While from single cell to mesoscopic levels temperature can directly be measured, at the system level of non-invasive studies using electroencephalogram or functional magnetic resonance, it can only be estimated indirectly, using the temperature dependence of the magnetic resonance signal's frequency (Hindman, 1966; Parker et al., 1983; Kuroda et al., 1996). Furthermore, a theoretical model of brain temperature (Yablonskiy et al., 2000; Sukstankii and Yablonskiy, 2006) allows inferring from functional magnetic resonance data that functional stimulation can induce local brain temperature fluctuations of up to ±1°C with respect to resting temperature, by locally changing the balance between metabolic heat production and heat removal by blood flow. The potential impact of temperature modulations on functional brain activity is significant. Given a temperature effect on blood oxygen saturation levels of several percent/1°C (Guyton, 1987), and an estimated average brain van't Hoff temperature coefficient Q10 (the factor by which a reaction rate increases for 10°C increases) of 2,3 (Swan, 1974), the observed temperature fluctuations may lead to sizeable changes in blood oxygen saturation levels and to >2% variations in chemical reaction rates. Here we propose a way to directly quantify temperature from system-level brain recordings, and show how it can be used to characterize neural activity associated with cognitive function.

Changes of intracellular potentials and ionic currents of the mollusk neurons under action of solvents dimethylsulfoxide and acetone

Dimethylsulfoxide (DMSO), and dimethyl ketone (acetone) in concentrations up to 100 mM after extracellular application did not change the electrical activity of the identified pedal ganglia neurons of clam Planorbarius corneus in microelectrode studies and voltage clamp technique. DMSO in concentrations of 500 and 1000 mM (4 and 8 % solution), and acetone in smaller concentrations (from 200 mM-1.2% or higher) was shown to depolarize neurons and to increase the frequency and duration of action potentials, their amplitude and the total ionic currents (dV/dt) being decreased. The changes were fully reversible, hyperpolarization of cells was registered after washing, which was caused probably by activation of electrogenic transport of sodium ions. DMSO and acetone were suggested to change the neuron state not only by changes in resting potential but also by direct effects on ion channels. Acetone reduced amplitude of action potentials in neurons because of depolarization and in less degree because of its effects on ion channels. DMSO and acetone in concentrations of 100-200 mM are concluded to be safe for biological objects when they are used for dissolution of pharmacological agents.

Shaping Synaptic Learning by the Duration of Postsynaptic Action Potential in a New STDP Model

Single spikes and their timing matter in changing synaptic efficacy, which is known as spike-timing-dependent plasticity (STDP). Most previous studies treated spikes as all-or-none events, and considered their duration and magnitude as negligible. Here we explore the effects of action potential (AP) duration on synaptic plasticity in a simplified model neuron using computer simulations. We propose a novel STDP model that depresses synapses using an AP duration dependent LTD window and induces potentiation of synaptic strength when presynaptic spikes arrive before and during a postsynaptic AP (dSTDP). We demonstrate that AP duration is another key factor for insensitizing the postsynaptic neural firing and for controlling the shape of synaptic weight distribution. Extended AP durations produce a wide unimodal weight distribution that resembles the ones reported experimentally and make the postsynaptic neuron tranquil when disturbed by poisson noise spike trains, while equivalently sensitive to the synchronized. Our results suggest that the impact of AP duration, modeled here as an AP-dependent STDP window, on synaptic plasticity can be dramatic and should motivate future STDP studies.

Pathophysiological changes in lumbar disc herniation

Objective To investigate pathophysiological changes in the multifidus muscles of patients with lumbar disc herniation.Methods Thirty-six patients with unilateral symptoms caused by lumbar disc herniation were enrolled.They were divided into a symptomatic side group and a contralateral side group according to whether their symptomatic (algetic) or contralateral side would be studied.The percentage area of pimelosis and the mean gross signal intensity of each multifidus were measured with magnetic resonance imaging (MRI)_ The amplitude and duration of motor unit potentials of each multifidus were recorded using electromyography (EMG) when the patients were performing isometric contraction.Results The bilateral multifidus muscles of 36 patients displayed various degrees of pimelosis on magnetic resonance images.The percentage of pimelosis cross-sectional area in the symptomatic side group was significantly higher than in the contralateral side group.[(44.20 ± 15.14)％ versus(37.31 ± 13.85)％,P ＜ 0.05] The mean value of the gross signal intensity was also significantly higher.Both the amplitudes and duration of the motor unit potentials recroded from the multifidus had increased and widened,but significantly more in the symptomatic side group than in the contralateral side group.Conclusions Both the imaging and electrophysiological data showed more significant changes on the symptomatic side in patients with unilateral symptoms caused by lumbar disc herniation. Key words: Multifidus; Unilateral symptoms; Lumbar disc herniation; Magnetic resonance imaging; Electromyography

Editors’ Pick: What a pain…, or not!

How nice, I thought as a child, would it be to not feel physical pain. Later I realized that sense of pain may exist for a reason; it was suggested that physical pain has evolved as an alarm system to protect the body from serious damage. Much later I read about human disorders involving severe insensitivity to physical pain. Still, the idea of not feeling pain remains appealing (especially anticipating my coming years when some painful age-related health problems are likely to kick in). Previously, it was demonstrated that a loss-of-function mutation in the sodium ion channel gene SCN9A leads to the inability to experience pain [1]. In a more recent study, Leipold et al.[2] identified another sodium ion channel gene, SCN11A, which, when harboring a particular missense mutation, causes loss of pain perception. SCN11A encodes the voltage-gated sodium ion channel NAv1.9, which is highly expressed in nociceptors (i.e., neurons that transmit sensory information from the body periphery to the spinal cord). The authors started out with whole-exome sequencing of healthy German parents and their child diagnosed with the congenital inability to experience pain. A heterozygote non-synonymous mutation in SCN11A was identified as the only de novo event detected in this affected child. Aiming to confirm this finding in independent samples, the authors performed Sanger sequencing of SCN11A exons in 58 additional individuals diagnosed with early-onset severe sensory loss, most of them representing sporadic cases. One Swedish individual showed the very same heterozygous SCN11A mutation, and the clinical history of both individuals was also similar. From these findings, the authors hypothesized that the identified mutation that leads to a replacement of leucine with proline (p.Leu811Pro) at the distal end of one of the transmembrane segments in domain II of NAv1.9 is disease causing and leads to loss of pain perception. Seeking molecular proof, the authors introduced the orthologous alteration (Leu799Pro) into the mouse Scn11a gene, but found no obvious morphological changes in sensory axons or in nerve fibers in the skin of the viable heterozygote knock-in mice. However, 11% of the knock-in mice had severe lesions that were not observed in the wild-type mice. Since the lesions also appeared in knock-in mice housed solitarily, it was assumed that they were self-inflicted. Also other experimental evidence pointed towards reduced pain sensitivity in these knock-in mice. Because NAv1.9 had been suggested to influence the excitability of dorsal root ganglia (DRG) neurons (i.e., their property to react to stimulation), the authors then investigated the electrical potential of DRG neurons isolated from wild-type and mutant mice. They found that a significant fraction of the mutant channels were active under resting conditions, and that the duration of action potentials was significantly reduced in the mutant neurons compared with wild-type neurons. In knock-out mice, however, only a minor effect on action potentials was observed. Additional experiments showed that the excessive activity at resting conditions caused sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. To study the effect of the mutation further, the authors heterologously expressed human NAv1.9 and NAv1.9 Leu811Pro mutant channels in ND7/23 cells (i.e., a mouse neuroblastoma x rat neuron hybrid cell line). They found that the phenotype of human NAv1.9 Leu811Pro mutant channels resembled that of mouse NAv1.9 Leu799Pro mutant channels, except in terms of steady-state inactivation. From the weak influence of the mutation on inactivation in the human channel, they concluded a stronger gain-of-function effect in humans than in knock-in mice. Besides impressively demonstrating the power of whole-exome sequencing to find rare candidate disease causing mutations, this study provides a new gain-of-function view on the molecular basis of pain loss, which was previously linked to loss-of-function mutations such as in the NAv1.7 channel encoded by SCN9A[1]. Furthermore, this finding may open up new avenues for the development of new painkilling drugs [3].

Electroneurography of the ulnar nerve in dogs

Electroneurography as one of the electrodiagnostic techniques is used to measure the speed of action potential which is propagated down the nerve after stimulation. It gives information about normal functioning of the peripheral nerves. The aim of this study was to evaluate the applicability of a new electroneurographic technique by performing motor nerve conduction velocity measurements in the ulnar nerve with surface stimulating electrodes in healthy dogs, to correlate the obtained data by age, limb length, rectal temperature, and sex; and to compare these results with published findings utilizing needle stimulating electrodes. The study was performed in 24 clinically healthy dogs without anaesthesia. Rectal temperatures and limb lengths were measured in all individuals. There were significant correlations among several indicators (age, rectal temperature, limb length, conduction velocity, latency and duration of compound muscle action potentials). Limb length was found to have a significant effect on the duration of the compound muscle action potential from both stimulation sites (proximal/distal; r = 0.71, r = 0.68, P &lt; 0.01), but there was no effect on the conduction velocity or amplitude of the action potentials. There was no significant difference (P &gt; 0.05) in the measured indicators between males and females, even though females had a higher mean conduction velocity than males. These results prove that conduction velocity measurements in dogs could be performed non-invasively, without a danger of infection or haematomas or complications with anaesthesia, which is more favourable and time-saving for clinical practice, and more comfortable for patients.

Assessing the Welfare Effects of Unemployment Benefits Using the Regression Kink Design

I show how, in the tradition of the dynamic labor supply literature, one can identify the moral hazard effects and liquidity effects of unemployment insurance (UI) using variations along the time profile of unemployment benefits. I use this strategy to investigate the anatomy of labor supply responses to UI. I identify the effect of benefit level and potential duration in the regression kink design using kinks in the schedule of benefits in the US. My results suggest that the response of search effort to UI benefits is driven as much by liquidity effects as by moral hazard effects. (JEL D82, J22, J65)

Impact of first-step potential and time on the vertical growth of ZnO nanorods on ITO substrate by two-step electrochemical deposition

Abstract In this study, we analyzed the growth of ZnO nanorods on an ITO (indium doped tin oxide) substrate by electrochemical deposition using a two-step, continuous potential process. We examined the effect of changing the first-step potential as well as the first-step duration on the morphological, structural and optical properties of ZnO nanorods, measured via using field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD) and photoluminescence (PL), respectively. As a result, vertical ZnO nanorods were grown on ITO substrate without the need for a template when the first-step potential was set to −1.2 V for a duration of 10 s, and the second-step potential was set to −0.7 V for a duration of 1190 s. The ZnO nanorods on this sample showed the highest XRD (0 0 2)/(1 0 0) peak intensity ratio and the highest PL near band edge emission to deep level emission peak intensity ratio (NBE/DLE). In this study, the nucleation for vertical ZnO nanorod growth on an ITO substrate was found to be affected by changes in the first-step potential and first-step duration.

WS2-1. A case of slowly progressive muscular atrophy in post hematopoietic stem cell transplantation: Electrophysiological and pathological findings in musculoskeletal chronic graft-versus-host disease (cGVHD)

A 38-year-old man who received bone marrow transplantation four years ago for acute lymphocytic leukemia. He felt muscle cramps and became a bed-bound state because of progressing polyarthralgia in the following year. Marked muscle atrophies, mild weakness, joint contractures, and sclerotic skin changes were noted. Motor conduction studies revealed reduction in the amplitude (2.4 mV), in the conduction velocity (41 m/s), and in the duration (11 ms) of compound muscle action potentials in the right median nerve. In concentric needle electromyography, low amplitude polyphasic motor unit potentials discharged with rapid frequency without spontaneous discharges. Mean muscle fiber CV elicited by monopolar needle electrodes were slow compared with normal control. The electrodiagnosis was myopathic change which consists of cluster of atrophic fibers, discriminated from myositis and motor neuron disease. Muscle specimen from autopsy revealed marked atrophied muscle fibers less than 10 μm in diameter. There were no necrotic and inflammatory processes. In the fascia, small numbers of infiltrating CD8 positive T lymphocytes with proliferation of collagen fibers were seen, compatible with fasciitis. There were few reports about electrophysiological and pathological findings of fasciitis in cGVHD, which must be focused on the future as distinct from the myositis.

P1-37. Distal compound muscle action potential dispersion would commonly occur in patients with anti-MAG/SGPG antibody associated neuropathy

The prolonged distal compound muscle action potential (CMAP) duration (i.e. distal temporal dispersion) has been recently validated as a measure of distal demyelination in chronic inflammatory demyelinating polyneuropathy (CIDP) patients. In previous reports, distal temporal dispersion was rare in patients with anti-MAG/SGPG antibody associated neuropathy. Here, to test this notion, we studied distal CMAP duration in our patients. Subjects were 5 patients with anti-MAG and/or anti-SGPG antibody associated neuropathy. We performed conventional motor conduction studies in unilateral median, ulnar and tibial nerves. The cut-off point of distal temporal dispersion was set at 9ms based on a previous report. Distal CMAP duration was prolonged in 4 of 5 patients. Among 13 responses, 50% (median), 60% (ulnar) and 75% (tibial) presented distal temporal dispersion. There were negative correlation between distal CMAP duration and conduction velocity (R[2] = 0.63, p = 0.0012), and positive correlation between distal CMAP duration and distal latency (R[2] = 0.75, p = 0.0001). Our findings suggest that distal temporal dispersion is not rare in patients with anti-MAG/SGPG antibody associated neuropathy, which is in contrast to previous reports.

Local activity in dendrites controls STDP by altering NMDA receptor kinetics

Spike timing-dependent plasticity (STDP) is a temporally asymmetric form of Hebbian plasticity in which the sign and magnitude of synaptic strength is determined by the precise timing between pre- and postsynaptic spikes. Postsynaptic NMDA receptors (NMDARs) play an important role in STDP due to their characteristic magnesium ion (Mg2+) gating process [1]. The Mg2+ gate is opened by near coincident presynaptic glutamate release and postsynaptic spiking. Contrary to previous belief, this gating process is not instantaneous but has distinct fast and slow time constants, which might influence the time window over which spike-EPSP coincidence occurs [2,3]. The aim of this study is to investigate how local activity in dendrites alters NMDAR kinetics and in turn controls the time window over which STDP occurs. Using a detailed biophysical model of an NR2A subunit, we find the NMDAR current to be temporally asymmetric with a faster block than unblock process. This is due to the voltage-dependent fast and slow time constants of Mg2+ gating. These time constants were on the order of 0.8 ms and 5 ms respectively and changed nonlinearly with membrane potential. By varying both amplitude and duration of a model action potential (AP), we find that dendritic Ca2+ spikes cause Mg2+ unblock to be dominated by its fast time constant. Conversely, somatic Na+ spikes elicit a slower unblocking. Since backpropagating APs (BAPs) attenuate along the dendritic arbor, our results suggest that NMDAR kinetics vary depending on synapse location. Next, we incorporated this biophysical model into a compartmentalized model of a neocortical pyramidal cell in order to investigate the effect that dendritic inhibition and synapse location has on STDP. NMDAR kinetics is significantly different in the basal and apical compartments, which gives rise to a heterogeneous set of STDP curves along the length of the dendrite. Distal synapses had a broader potentiation window than apical synapses, suggesting that distal branches are less selective to correlated inputs. This synapse-location dependent STDP learning rule agrees with previous findings [4]. Dendritic inhibition plays an important role in shaping the computations performed by pyramidal neurons in the neocortex. However, the role that inhibition plays in controlling synaptic plasticity is less clear. By incorporating inhibitory synapses in our model, we find that varying the timing of inhibition relative to the EPSP shifted the peak of the STDP curve, resulting in a reversal of the temporal order of depression and potentiation. Inhibition altered NMDAR kinetics by increasing its blocking rate. As a result, changing the balance between excitation and inhibition in the dendritic branch results in a sliding threshold between LTP and LTD. In summary, we show that NMDAR kinetics can be altered in an activity-dependent manner resulting in different STDP learning rules. When taken in context of the BCM theory, our finding implies that dendritic inhibition can dynamically alter the threshold between LTP and LTD by altering the time constants of the NMDAR. Our model provides a novel framework for understanding how STDP in different dendritic compartments selects inputs alters information processing in individual neurons.