bluuebunny/crossref_metadata_2025 huggingface dataset:
GBT1118, a potent allosteric modifier of hemoglobin O2affinity, increases tolerance to severe hypoxia in mice
Authors: Dufu Kobina , Yalcin Ozlem , Ao-ieong Eilleen S. Y. , Hutchaleelala Athiwat , Xu Qing , Li Zhe , Vlahakis Nicholas , Oksenberg Donna , Lehrer-Graiwer Josh , Cabrales Pedro
Published: May 2017

Adaptation to hypoxia requires compensatory mechanisms that affect O2transport and utilization. Decreased hemoglobin (Hb) O2affinity is considered part of the physiological adaptive process to chronic hypoxia. However, this study explores the hypothesis that increased Hb O2affinity can complement acute physiological responses to hypoxia by increasing O2uptake and delivery compared with normal Hb O2affinity during acute severe hypoxia. To test this hypothesis, Hb O2affinity in mice was increased by oral administration of 2-hydroxy-6-{[(2 S)-1-(pyridine-3-carbonyl)piperidin-2yl] methoxy}benzaldehyde (GBT1118; 70 or 140 mg/kg). Systemic and microcirculatory hemodynamics and oxygenation parameters were studied during hypoxia in awake-instrumented mice. GBT1118 increased Hb O2affinity and decreased the Po2at which 50% of Hb is saturated with O2(P50) from 43 ± 1.1 to 18.3 ± 0.9 mmHg (70 mg/kg) and 7.7 ± 0.2 mmHg (140 mg/kg). In a dose-dependent fashion, GBT1118 increased arterial O2saturation by 16% (70 mg/kg) and 40% (140 mg/kg) relative to the control group during 5% O2hypoxia. In addition, a GBT1118-induced increase in Hb O2affinity reduced hypoxia-induced hypotension compared with the control group. Moreover, microvascular blood flow was higher during hypoxia in GBT1118-treated groups than the control group. The increased O2saturation and improved blood flow in GBT1118-treated groups preserved higher interstitial tissue Po2than in the control group during 5% O2hypoxia. In conclusion, increased Hb O2affinity enhanced physiological tolerance to hypoxia, as evidenced by improved hemodynamics and tissue oxygenation. Therefore, pharmacologically induced increases in Hb O2affinity become a potential therapeutic approach to improve tissue oxygenation in pulmonary diseases characterized by severe hypoxemia.

NEW & NOTEWORTHY This study establishes that pharmacological modification of hemoglobin O2affinity can be a promising and novel therapeutic strategy for the treatment of hypoxic hypoxia and paves the way for the clinical development of molecules that prevent hypoxemia.
Decoding Neural Spike Trains: Calculating the Probability That a Spike Train and an External Signal Are Related
Authors: Sanger Terence D.
Published: May 2017

Experimental and clinical applications of extracellular recordings of spiking cell activity frequently are used to relate the activity of a cell to externally measurable signals such as surface potentials, sensory stimuli, or movement measurements. When the external signal is time-varying, correlation methods have traditionally been used to quantify the degree of relation with the neural firing. However, in some circumstances correlation methods can give misleading results. A new algorithm is described that estimates the extent to which a spike train is related to a continuous time-varying signal. The technique calculates the probability of generating a spike train with Poisson statistics if the time-varying signal determines the Poisson rate. This is accomplished by successive division of the signal and the spike train into halves and recursive calculation of the probability of each half-signal. The performance of the new algorithm is compared with the performance of correlation methods on simulated data.
Computational Studies on Acquisition and Adaptation of Ocular Following Responses Based on Cerebellar Synaptic Plasticity
Authors: Yamamoto Kenji , Kobayashi Yasushi , Takemura Aya , Kawano Kenji , Kawato Mitsuo
Published: May 2017

To investigate how cerebellar synaptic plasticity guides the acquisition and adaptation of ocular following response (OFR), a large-scale network model was developed. The model includes the cerebral medial superior temporal area (MST), Purkinje cells (P cells) of the ventral paraflocculus, the accessory optic and climbing fiber systems, the brain stem oculomotor network, and the oculomotor plant. The model reconstructed temporal profiles of both firing patterns of MST neurons and P cells and eye movements. Model MST neurons ( n = 1,080) were set to be driven by retinal error and exhibited 12 preferred directions, 30 preferred velocities, and 3 firing waveforms. Correspondingly, each model P cell contained 1,080 excitatory synapses from granule cell axons (GCA) and 1,080 inhibitory synapses. P cells ( n = 40) were classified into four groups by their laterality (hemisphere) and by preferred directions of their climbing fiber inputs (CF) (contralateral or upward). The brain stem neural circuit and the oculomotor plant were modeled on the work of Yamamoto et al. The initial synaptic weights on the P cells were set randomly. At the beginning, P cell simple spikes were not well modulated by visual motion, and the eye was moved only slightly by the accessory optic system. The synaptic weights were updated according to integral-differential equation models of physiologically demonstrated synaptic plasticity: long-term depression and long-term potentiation for GCA synapses and rebound potentiation for inhibitory synapses. We assumed that maximum plasticity was induced when GCA inputs preceded CF inputs by 200 ms. After more than 10,000 presentations of ramp-step visual motion, the strengths of both the excitatory and inhibitory synapses were modified. Subsequently, the simple spike responses became well developed, and ordinary OFRs were acquired. The preferred directions of simple spikes became the opposite of those of CFs. Although the model MST neurons were set to possess a wide variety of firing characteristics, the model P cells acquired only downward or ipsilateral preferred directions, high preferred velocities and stereotypical firing waveforms. Therefore the drastic transition of the neural representation from the population codes in the MST to the firing-rate codes of simple spikes were learned at the GCA-P cell synapses and inhibitory cells-P cell synapses. Furthermore, the model successfully reproduced the gain- and directional-adaptation of OFR, which was demonstrated by manipulating the velocity and direction of visual motion, respectively. When we assumed that synaptic plasticity could only occur if CF inputs preceded GCA inputs, the ordinary OFR were acquired but neither the gain-adaptation nor the directional adaptation could be reproduced.
Different Mechanisms of Calcium Entry Within Different Dendritic Compartments
Authors: Single Sandra , Borst Alexander
Published: May 2017

From our experiments combining in vivo calcium imaging and electrophysiology on fly vertical motion-sensitive cells (VS-cells) during visual stimulation, we infer different mechanisms of calcium entry within different dendritic compartments; while in the main dendritic branches calcium influx from extracellular space takes place only via voltage-activated calcium channels (VACCs), calcium enters the dendritic tips through VACCs as well as nicotinic acetylcholine receptors (nAChRs). Consequently, neuronal nACHRs of insects have to be assumed to be permeable to some extent for calcium under in vivo conditions.
Cerebellar Damage Impairs Automaticity of a Recently Practiced Movement
Authors: Lang Catherine E. , Bastian Amy J.
Published: May 2017

It has been suggested that the cerebellum plays a critical role in learning to make movements more “automatic” (i.e., requiring less attention to the details of a movement). We hypothesized that cerebellar damage compromises learning of movement automaticity, resulting in increased attentional demands for movement control. The purpose of our study was to determine whether cerebellar damage disrupts the ability to make a practiced movement more automatic. We developed a dual task paradigm using two tasks that did not have overlapping sensory or motor requirements for execution. Our motor task required subjects to maintain an upright posture while performing a figure-8 movement using their arm. This motor task was chosen to simulate requirements of everyday movements (e.g., standing while reaching for objects), but it was novel enough to require practice for improvement. Our secondary task was an auditory vigilance task where subjects listened to letter sequences and were asked to identify the number of times a target letter was heard. We tested controls and people with cerebellar damage as they practiced the movement task alone and then performed it with the auditory task. We recorded 3D position data from the arm, trunk, and leg during the movement task. Errors were recorded for both the movement and the letter tasks. Our results show that cerebellar subjects can improve the movement to a very limited extent with practice. Unlike controls, the motor performance of cerebellar subjects deteriorates to prepractice levels when attention is focused away from the movement during dual task trials. Control subjects' insensitivity to dual task interference after practice was due to learned movement automaticity and was not a reflection of better dual task performance generally. Overall, our findings suggest that the cerebellum may be important for shifting movement performance from an attentionally demanding (unpracticed) state to a more automatic (practiced) state.
Responses of Superficial Dorsal Horn Neurons to Intradermal Serotonin and Other Irritants: Comparison With Scratching Behavior
Authors: Jinks Steven L. , Carstens E.
Published: May 2017

Scratching behavior is used to assess itch sensation in animals, but few studies have addressed the relative scratch-inducing capacity of different algesic and pruritic chemicals. Furthermore, central neural mechanisms underlying itch are not well understood. We used electrophysiological and behavioral methods to investigate the ability of several irritant chemicals to excite neurons in the superficial dorsal horn, as well as to elicit scratching, in rats. In anesthetized rats, single neurons in the superficial lumbar dorsal horn, identified by their responsiveness to intracutaneous (ic) histamine, were classified as wide dynamic range (WDR) or nociceptive-specific (NS). Serotonin (5-HT) given ic to the paw excited most (88%) WDR and NS neurons over a prolonged time course (often up to 40 min). 5-HT–evoked responses exhibited significant tachyphylaxis. Most neurons also gave shorter-duration responses to ic capsaicin (92%) and mustard oil (71%). In separate behavioral experiments, significant dose-related hind limb scratching directed at the ic injection site in the back of the neck was elicited by 5-HT over a time course similar to that of evoked neuronal firing. A second 5-HT injection made 40 min later at the same site elicited significantly less scratching. Formalin also elicited scratching that was not dose-related and less than that evoked by 5-HT. 5-HT and Formalin also evoked head or whole-body shakes that were significantly correlated with scratching. Neither histamine, capsaicin, nor vehicle controls elicited significant scratching or shaking. In rats, 5-HT appears to be more pruritogenic than histamine as assessed by scratching and shaking behavior, and excites superficial dorsal horn neurons over a behaviorally relevant time course. However, because most neurons additionally responded to pain-producing stimuli, they are not itch-specific. They might nonetheless contribute to neural pathways that distinguish between pain and itch based on some neural mechanism such as frequency coding.
Effects of Methylphenidate on the Membrane Potential and Current in Neurons of the Rat Locus Coeruleus
Authors: Ishimatsu Masaru , Kidani Yuri , Tsuda Akira , Akasu Takashi
Published: May 2017

Effects of methylphenidate (MPH), a therapeutic agent used in children presenting the attention deficit hyperactivity disorder (ADHD), on the membrane potential and current in neurons of the rat locus coeruleus (LC) were examined using intracellular and whole cell patch-clamp recording techniques. Application of MPH (30 μM) to artificial cerebrospinal fluid (ACSF) produced a hyperpolarizing response with amplitude of 12 ± 1 mV ( n = 29). Spontaneous firing of LC neurons was blocked during the MPH-induced hyperpolarization. Superfusion of LC neurons with ACSF containing 0 mM Ca2+ and 11 mM Mg2+ (Ca2+-free ACSF) produced a depolarizing response associated with an increase in spontaneous firing of the action potential. The MPH-induced hyperpolarization was blocked in Ca2+-free ACSF. Yohimbine (1 μM) and prazosin (10 μM), antagonists for α2 and α2B/2Creceptors, respectively, blocked the MPH-induced hyperpolarization in LC neurons. Tetrodotoxin (TTX, 1 μM) produced a partial depression of the MPH-induced hyperpolarization in LC neurons. Under the whole cell patch-clamp condition, MPH (30–300 μM) produced an outward current ( I MPH) with amplitude of 110 ± 6 pA ( n = 17) in LC neurons. The I MPH was blocked by Co2+ (1 mM). During prolonged application of MPH (300 μM for 45 min), the hyperpolarization gradually decreased in the amplitude and eventually disappeared, possibly because of depression of norepinephrine (NE) release from noradrenergic nerve terminals. At a low concentration (1 μM), MPH produced no outward current but consistently enhanced the outward current induced by NE. These results suggest that the MPH-induced response is mediated by NE via α2B/2C-adrenoceptors in LC neurons. I MPH was associated with an increase in the membrane conductance of LC neurons. The I MPH reversed its polarity at −102 ± 6 mV ( n = 8) in the ACSF. The reversal potential of I MPH was changed by 54 mV per decade change in the external K+ concentration. Current-voltage relationship showed that the I MPH exhibited inward rectification. Ba2+ (100 μM) suppressed the amplitude and the inward rectification of the I MPH.These results suggest that the I MPH is produced by activation of inward rectifier K+channels in LC neurons.
Influence of Reward Expectation on Visuospatial Processing in Macaque Lateral Prefrontal Cortex
Authors: Kobayashi Shunsuke , Lauwereyns Johan , Koizumi Masashi , Sakagami Masamichi , Hikosaka Okihide
Published: May 2017

The lateral prefrontal cortex (LPFC) has been implicated in visuospatial processing, especially when it is required to hold spatial information during a delay period. It has also been reported that the LPFC receives information about expected reward outcome. However, the interaction between visuospatial processing and reward processing is still unclear because the two types of processing could not be dissociated in conventional delayed response tasks. To examine this, we used a memory-guided saccade task with an asymmetric reward schedule and recorded 228 LPFC neurons. The position of the target cue indicated the spatial location for the following saccade and the color of the target cue indicated the reward outcome for a correct saccade. Activity of LPFC was classified into three main types: S-type activity carried only spatial signals, R-type activity carried only reward signals, and SR-type activity carried both. Therefore only SR-type cells were potentially involved in both visuospatial processing and reward processing. SR-type activity was enhanced (SR+) or depressed (SR−) by the reward expectation. The spatial discriminability as expressed by the transmitted information was improved by reward expectation in SR+ type. In contrast, when reward information was coded by an increase of activity in the reward-absent condition (SR− type), it did not improve the spatial representation. This activity appeared to be involved in gaze fixation. These results extend previous findings suggesting that the LPFC exerts dual influences based on predicted reward outcome: improvement of memory-guided saccades (when reward is expected) and suppression of inappropriate behavior (when reward is not expected).
Activity-Dependent Plasticity of Calcium Clearance From Crayfish Motor Axons
Authors: Fengler Brian T. , Lnenicka Gregory A.
Published: May 2017

Previous studies of a crayfish explant culture demonstrated that regenerating motor axons with high impulse activity develop more rapid clearance of cytoplasmic free Ca2+than those with low impulse activity. We examined whether Ca2+clearance in mature axons also showed activity-dependent plasticity. We studied the phasic and tonic axons of the motor bundle innervating the crayfish closer muscle that display large differences in impulse activity. To compare their Ca2+regulation, we applied the Ca2+ionophore Br-23187 (1 μM) and measured the increase in intracellular free Ca2+concentration ([Ca2+]i) with fura-2. After 55 min of ionophore application, the increase in [Ca2+]iin the phasic axons (1,326 ± 192 nM) was significantly greater than in the tonic axons (359 ± 148 nM). This resulted from stronger Ca2+clearance in the tonic axon rather than less Ca2+influx because blocking Ca2+clearance by Na/Ca exchange and mitochondria eliminated these differences in [Ca2+]i. Next we determined whether Ca2+clearance from the phasic axon could be strengthened by a prolonged increase in impulse activity. The phasic axon was stimulated in vivo at 5 Hz for 1 h/day for 5 days, and 1–3 days after stimulation, Ca2+clearance was again examined. After 55 min of Br-23187 (1 μM) exposure, the increase in [Ca2+]iin the stimulated phasic axon was only 232 ± 123 nM, which was much less than in the control phasic axons and similar to that in the tonic axons. Thus Ca2+-clearance mechanisms adapt to changes in impulse activity both in growing and mature axons.
Changes in Calcium Signaling During Postembryonic Dendritic Growth inManduca sexta
Authors: Duch C. , Levine R. B.
Published: May 2017

Activity-dependent Ca2+influx plays crucial roles in adult and developing nervous systems through its influence on signal processing, synaptic plasticity, and neuronal differentiation. The responses to internal Ca2+elevations vary depending on the spatial distribution of Ca2+accumulation in different cell compartments. In this study, the mechanisms and the distribution of Ca2+accumulation are addressed by in situ Ca2+imaging of an identified insect motoneuron, MN5, at critical stages of postembryonic life. During metamorphosis of Manduca sexta, MN5 undergoes extensive dendritic regression followed by regrowth. The time course, amplitude, and distribution of Ca2+accumulation within MN5 change during development. During the initial stage of rapid dendritic growth and branching, dendritic growth cones are present, and voltage-dependent Ca2+currents are small. At this stage, activity-induced elevations of internal Ca2+are largest in the distal dendrites, suggesting that the density of voltage-gated Ca2+channels is highest in these regions. Later phases of dendritic growth are accompanied by the transient occurrence of prominent Ca2+spikes. Single Ca2+spikes cause robust Ca2+influx of similar amplitudes and time courses in all central compartments of MN5. The resting Ca2+levels also increase during development. Ca2+-induced Ca2+release from intracellular stores did not contribute to the elevations measured at either stage, although Ca2+stores are present in the dendrites. These developmental changes of the internal Ca2+signaling are consistent with a regulatory role for activity-dependent Ca2+influx in postembryonic dendritic growth.
Resilient RTN Fast Spiking in Kv3.1 Null Mice Suggests Redundancy in the Action Potential Repolarization Mechanism
Authors: Porcello Darrell M. , Ho Chi Shun , Joho Rolf H. , Huguenard John R.
Published: May 2017

Fast spiking (FS), GABAergic neurons of the reticular thalamic nucleus (RTN) are capable of firing high-frequency trains of brief action potentials, with little adaptation. Studies in recombinant systems have shown that high-voltage-activated K+ channels containing the Kv3.1 and/or Kv3.2 subunits display biophysical properties that may contribute to the FS phenotype. Given that RTN expresses high levels of Kv3.1, with little or no Kv3.2, we tested whether this subunit was required for the fast action potential repolarization mechanism essential to the FS phenotype. Single- and multiple-action potentials were recorded using whole-cell current clamp in RTN neurons from brain slices of wild-type and Kv3.1-deficient mice. At 23°C, action potentials recorded from homozygous Kv3.1 deficient mice (Kv3.1−/−) compared with their wild-type (Kv3.1+/+) counterparts had reduced amplitudes (−6%) and fast after-hyperpolarizations (−16%). At 34°C, action potentials in Kv3.1−/− mice had increased duration (21%) due to a reduced rate of repolarization (−30%) when compared with wild-type controls. Action potential trains in Kv3.1−/− were associated with a significantly greater spike decrement and broadening and a diminished firing frequency versus injected current relationship ( F/I) at 34°C. There was no change in either spike count or maximum instantaneous frequency during low-threshold Ca2+ bursts in Kv3.1−/− RTN neurons at either temperature tested. Our findings show that Kv3.1 is not solely responsible for fast spikes or high-frequency firing in RTN neurons. This suggests genetic redundancy in the system, possibly in the form of other Kv3 members, which may suffice to maintain the FS phenotype in RTN neurons in the absence of Kv3.1.
Mitochondrial Ca2+Buffering Regulates Synaptic Transmission Between Retinal Amacrine Cells
Authors: Medler Kathryn , Gleason Evanna L.
Published: May 2017

The diverse functions of retinal amacrine cells are reliant on the physiological properties of their synapses. Here we examine the role of mitochondria as Ca2+buffering organelles in synaptic transmission between GABAergic amacrine cells. We used the protonophore p-trifluoromethoxy-phenylhydrazone (FCCP) to dissipate the membrane potential across the inner mitochondrial membrane that normally sustains the activity of the mitochondrial Ca2+uniporter. Measurements of cytosolic Ca2+levels reveal that prolonged depolarization-induced Ca2+elevations measured at the cell body are altered by inhibition of mitochondrial Ca2+uptake. Furthermore, an analysis of the ratio of Ca2+efflux on the plasma membrane Na-Ca exchanger to influx through Ca2+channels during voltage steps indicates that mitochondria can also buffer Ca2+loads induced by relatively brief stimuli. Importantly, we also demonstrate that mitochondrial Ca2+uptake operates at rest to help maintain low cytosolic Ca2+levels. This aspect of mitochondrial Ca2+buffering suggests that in amacrine cells, the normal function of Ca2+-dependent mechanisms would be contingent upon ongoing mitochondrial Ca2+uptake. To test the role of mitochondrial Ca2+buffering at amacrine cell synapses, we record from amacrine cells receiving GABAergic synaptic input. The Ca2+elevations produced by inhibition of mitochondrial Ca2+uptake are localized and sufficient in magnitude to stimulate exocytosis, indicating that mitochondria help to maintain low levels of exocytosis at rest. However, we found that inhibition of mitochondrial Ca2+uptake during evoked synaptic transmission results in a reduction in the charge transferred at the synapse. Recordings from isolated amacrine cells reveal that this is most likely due to the increase in the inactivation of presynaptic Ca2+channels observed in the absence of mitochondrial Ca2+buffering. These results demonstrate that mitochondrial Ca2+buffering plays a critical role in the function of amacrine cell synapses.
Silent Synapses in Developing Cerebellar Granule Neurons
Authors: Losi Gabriele , Prybylowski Kate , Fu ZhanYan , Luo Jian Hong , Vicini Stefano
Published: May 2017

Silent synapses are excitatory synapses endowed exclusively with N-methyl-d-aspartate (NMDA) responses that have been proposed to acquire α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses during development and after long-term potentiation (LTP). These synapses are functionally silent because of the Mg2+ block of NMDA receptors at resting potentials. Here we provide evidence for the presence of silent synapses in developing cerebellar granule cells. Using the patch-clamp technique in the whole-cell configuration, we recorded the spontaneous excitatory postsynaptic currents (sEPSCs) from rat cerebellar granule cells in culture and in slices at physiological concentration of Mg2+ (1 mM). A holding potential of +60 mV removes Mg2+ block of NMDA channels, allowing us to record NMDA-sEPSCs. We thus compared the frequency of AMPA-sEPSCs, recorded at −60 mV, with that of NMDA-sEPSCs, recorded at +60 mV. NMDA-sEPSCs occurred at higher frequency than the AMPA-sEPSCs in most cells recorded in slices from rats at postnatal day (P) <13 and in culture at 6–8 days after plating (DIV6–8). In a few cells from young rats (P6–9) and in most neurons in culture at DIV6 we recorded exclusively NMDA-sEPSCs, supporting the hypothesis of existence of functional synapses with NMDA and without AMPA receptors. Increasing glutamate release in the slice with cyclothiazide and temperature increased AMPA and NMDA-sEPSCs frequencies but failed to alter the relative ratio of frequency of occurrence. Frequency ratio of NMDA versus AMPA-sEPSCs in slices was correlated with the weighted time constant of decay (τ w ) of NMDA-sEPSCs and decreased with development along the reported decrease of τ w . We suggest that the prevalence of synaptic NR2A subunits that confer faster kinetics is paralleled by the disappearance of silent synapses early in cerebellar development.
Postsynaptic Induction and Presynaptic Expression of Group 1 mGluR-Dependent LTD in the Hippocampal CA1 Region
Authors: Watabe Ayako M. , Carlisle Holly J. , O'Dell Thomas J.
Published: May 2017

Activation of metabotropic glutamate receptors (mGluRs) with the group I mGluR selective agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) induces a long-term depression (LTD) of excitatory synaptic transmission in the CA1 region of the hippocampus. Here we investigated the potential roles of pre- and postsynaptic processes in the DHPG-induced LTD at excitatory synapses onto hippocampal pyramidal cells in the mouse hippocampus. Activation of mGluRs with DHPG, but not ACPD, induced LTD at both Schaffer collateral/commissural fiber synapses onto CA1 pyramidal cells and at associational/commissural fiber synapses onto CA3 pyramidal cells. DHPG-induced LTD was blocked when the G-protein inhibitor guanosine-5′- O-(2-thiodiphosphate) was selectively delivered into postsynaptic CA1 pyramidal cells via an intracellular recording electrode, suggesting that DHPG depresses synaptic transmission through a postsynaptic, GTP-dependent signaling pathway. The effects of DHPG were also strongly modulated, however, by experimental manipulations that altered presynaptic calcium influx. In these experiments, we found that elevating extracellular Ca2+ concentrations ([Ca2+]o) to 6 mM almost completely blocked the effects of DHPG, whereas lowering [Ca2+]o to 1 mM significantly enhanced the ability of DHPG to depress synaptic transmission. Enhancing Ca2+ influx by prolonging action potential duration with bath applications of the K+ channel blocker 4-aminopyridine (4-AP) also strongly reduced the effects of DHPG in the presence of normal [Ca2+]o (2 mM). Although these findings indicate that alterations in Ca2+-dependent signaling processes strongly regulate the effects of DHPG on synaptic transmission, they do not distinguish between potential pre- versus postsynaptic sites of action. We found, however, that while inhibiting both pre- and postsynaptic K+ channels with bath-applied 4-AP blocked the effects of DHPG; inhibition of postsynaptic K+channels alone with intracellular Cs+ and TEA had no effect on the ability of DHPG to inhibit synaptic transmission. This suggests that presynaptic changes in transmitter release contribute to the depression of synaptic transmission by DHPG. Consistent with this, DHPG induced a persistent depression of both AMPA and N-methyl-d-aspartate receptor-mediated components of excitatory postsynaptic currents in voltage-clamped pyramidal cells. Together our results suggest that activation of postsynaptic mGluRs suppresses transmission at excitatory synapses onto CA1 pyramidal cells through presynaptic effects on transmitter release.
3D Evaluation of Palatal Rugae in Identical Twins
Authors: Taneva Emiliya , Evans Carla , Viana Grace
Published: May 2017

The study of identical twins can point out potential limitations in biometrics and forensic odontology. This case report presents three-dimensional (3D) palatal rugae analysis in monozygotic twins utilizing digital models obtained directly by scanning the maxillary dental arch with the iTero® intraoral digital scanner. The results show that the rugae patterns contain related but not identical features between the pair of identical twins. Dental study models taken on a regular basis for diagnosis and treatment planning in dentistry include the palatal rugae, which could be valuable to forensics in identical twin identification cases.
Effect of Artificial Aging Protocols on Surface Gloss of Resin Composites
Authors: Rocha Rafael Santos , Oliveira Amanda Carvalho , Caneppele Taciana Marco Ferraz , Bresciani Eduardo
Published: May 2017

The purpose of this study was to evaluate the effect of aging protocols on surface gloss of composites. Cylindrical resin composite specimens (6 mm in diameter, 1 mm thick) were fabricated and divided into three groups (N=60): microfilled (MiFi), nanohybrid (NaHy), and nanofilled (NaFi). Specimens were distributed into four aging subgroups: thermocycling (5° to 55°C, 15,000 cycles); ethanol immersion (15 days); brushing (10,750 cycles); and light aging (216 h). Surface gloss readings (Novo-Curve, Rhopoint TM, England) were performed at baseline (R0) and after every one-third of aging protocols (R1 to R3). Data were submitted to one-way repeated measures ANOVA and Tukey’s test (5%). Overall, surface gloss alterations were detected over time (p<0.001). Thermocycling reduced surface gloss, except for NaHy. Ethanol immersion resulted in surface gloss reduction after R1 for MiFi and NaFi, while reduction after R1 and R2 was detected for NaHy. For brushing, gloss reduction was detected after R1 and R3 for all composites. For light aging, gloss was reduced after R1 and R2 for MiFi and NaFi, while a reduction only after R1 was detected for NaHy. The studied aging protocols affect surface gloss differently, being material and aging therapy dependent. In general, the surface gloss is reduced with aging.
Nonparametric Subgroup Identification by PRIM and CART: A Simulation and Application Study
Authors: Ott Armin , Hapfelmeier Alexander
Published: May 2017

Two nonparametric methods for the identification of subgroups with outstanding outcome values are described and compared to each other in a simulation study and an application to clinical data. The Patient Rule Induction Method (PRIM) searches for box-shaped areas in the given data which exceed a minimal size and average outcome. This is achieved via a combination of iterative peeling and pasting steps, where small fractions of the data are removed or added to the current box. As an alternative, Classification and Regression Trees (CART) prediction models perform sequential binary splits of the data to produce subsets which can be interpreted as subgroups of heterogeneous outcome. PRIM and CART were compared in a simulation study to investigate their strengths and weaknesses under various data settings, taking different performance measures into account. PRIM was shown to be superior in rather complex settings such as those with few observations, a smaller signal-to-noise ratio, and more than one subgroup. CART showed the best performance in simpler situations. A practical application of the two methods was illustrated using a clinical data set. For this application, both methods produced similar results but the higher amount of user involvement of PRIM became apparent. PRIM can be flexibly tuned by the user, whereas CART, although simpler to implement, is rather static.
Dynamic Modeling and Control Characteristics of the Two-Modular HTR-PM Nuclear Plant
Authors: Dong Zhe , Pan Yifei , Song Maoxuan , Huang Xiaojing , Dong Yujie , Zhang Zuoyi
Published: May 2017

The modular high temperature gas-cooled reactor (MHTGR) is a typical small modular reactor (SMR) with inherent safety feature. Due to its high reactor outlet coolant temperature, the MHTGR can be applied not only for electricity production but also as a heat source for industrial complexes. Through multimodular scheme, that is, the superheated steam flows produced by multiple MHTGR-based nuclear supplying system (NSSS) modules combined together to drive a common thermal load, the inherent safety feature of MHTGR is applicable to large-scale nuclear plants at any desired power ratings. Since the plant power control technique of traditional single-modular nuclear plants cannot be directly applied to the multimodular plants, it is necessary to develop the power control method of multimodular plants, where dynamical modeling, control design, and performance verification are three main aspects of developing plant control method. In this paper, the study in the power control for two-modular HTR-PM plant is summarized, and the verification results based on numerical simulation are given. The simulation results in the cases of plant power step and ramp show that the plant control characteristics are satisfactory.
Investigation of Various Cross-Linking Methods for the Immobilization of Cytosine Arabinoside on Bacterial Magnetosomes
Authors: Dai Qinglei , Ma Yiming , Wang Shibin , Kankala Ranjith Kumar , Liu Yuangang
Published: May 2017

Bacterial magnetosomes (BMs) have emerged as potential drug delivery vehicles, possessing an iron oxide or iron sulfide core surrounded by a natural lipid membrane shell. In this study, we immobilized cytosine arabinoside (Ara-C) effectively on BMs by using various methods such as direct absorption (ABMs), and others include different cross-linkers such as genipin (GP) and glutaraldehyde (G). A well-dispersed Ara-C coupled bacterial magnetosomes resulted in significantly higher negative charge than that of naked BMs (−11.5±0.3 mV) confirming the drug loading. Out of all methods, direct absorption process led to the highest encapsulation efficiency and drug loading of88.2±4.3% and46.9±1.2%, respectively. These designs have shown the long-term drug release behavior without an initial burst release. Our results indicate that BMs-based nanoconjugates will potentially find widespread applications in pharmaceutical field.
Chronic Kidney Dysfunction Can Increase the Risk of Deep Vein Thrombosis after Total Hip and Knee Arthroplasty
Authors: Li Qiangqiang , Dai Bingyang , Yao Yao , Song Kai , Chen Dongyang , Jiang Qing
Published: May 2017

Background. Deep vein thrombosis (DVT) is one of the major complications of total joint arthroplasty (TJA). Chronic kidney dysfunction (CKD) has proven to promote a proinflammatory and prothrombotic state and is prevalent among patients undergoing TJA. The purpose of this study is to identify whether CKD increase the risk of DVT following TJA. Methods. In a retrospective study, 1274 patients who underwent primary TJA were studied. CKD is graded in 5 stages. Univariate and multivariate analysis were used to identify the association of CKD and its severity with postoperative DVT. Results. There were 1139 (89.4%) participants with normal kidney function, 103 (8.1%) with mildly decreased kidney function, and 32 (2.5%) with stage 3 and 4 CKD. A total of 244 patients (19.2%) were diagnosed with DVT. Sixty-four patients (5.0%) developed symptomatic DVT. Advanced age, female gender, malignancy, and eGFR showed significant association with total DVT. BMI, thrombosis history, malignancy, and eGFR were associated with symptomatic DVT. After adjusting for age, gender, BMI, and malignancy, eGFR was found to be related to both total and symptomatic DVT. Conclusions. CKD is an important risk factor for both total and symptomatic DVT following TJA. Postoperative prophylaxis should be made a priority in this population.
Spontaneous Rupture of Renal Metastasis from Hepatocellular Carcinoma
Authors: Kinoshita Osamu , Ichijo Yusuke , Yoneda Masayuki , Ikai Atsushi , Yamashita Tetsuro
Published: May 2017

We report a rare life-threatening case of spontaneous rupture of renal metastasis from hepatocellular carcinoma (HCC) that was managed by emergent transcatheter arterial embolization (TAE). A 76-year-old woman diagnosed with HCC presented with acute back pain in her right side and was transferred to our hospital. Initial enhanced computed tomography revealed retroperitoneal hemorrhage from the right kidney, which was retrospectively diagnosed as a spontaneous rupture of the metastatic renal tumor from the primary HCC. Detailed examination identified an active retroperitoneal hemorrhage from the lesion and the patient’s condition became hemodynamically unstable; hence emergent TAE was performed. The hospitalization period after the TAE was uneventful and sorafenib was subsequently administered. Unfortunately, two months after the TAE, the tumor locally progressed within the retroperitoneal space. Tumors were controlled by repeated TAE as the patient did not want to undergo a nephrectomy. Consequently, she survived for more than one year after emergent TAE, exhibiting low levels of tumor marker. After rupture of the metastatic renal HCC, tumors were expected to progress into the retroperitoneal space, and nephrectomy was the next possible radical treatment to offer the best chance of long-term disease control.
Gamma Knife Radiosurgery for Vestibular Schwannomas and Quality of Life Evaluation
Authors: Berkowitz Oren , Han Yueh-Ying , Talbott Evelyn O. , Iyer Aditya K. , Kano Hideyuki , Kondziolka Douglas , Brown Mason A. , Lunsford L. Dade
Published: May 2017

Background: Further investigation is needed to look at the impact of vestibular schwannoma (VS) on the health-related quality of life (QOL) of participants who undergo Gamma Knife® radiosurgery (GKRS). Objectives: Investigators compared the QOL for VS participants to reported US population norms in order to evaluate disease burden and long-term QOL several years after GKRS. Methods: This cross-sectional study surveyed participants to assess hearing status, tinnitus, imbalance, vertigo, as well as the Short-Form 36-item Health Questionnaire (SF-36). The data were normalized, age adjusted, and functional status was correlated to determine clinically significant differences. Results: A total of 353 participants who underwent GKRS between 1997 and 2007 were included in this study with a median postoperative period of 5 years. SF-36 scores were very similar to population norms, and age-adjusted scores for participants followed the US population curve. Frequent vertigo and balance problems had the largest statistically and clinically significant effect on physical and mental component summary scores followed by nonuseful hearing in the tumor ear. Conclusions: Participants reported a good long-term QOL that was very similar to the QOL of US population norms. Of the common VS symptoms, vertigo had the greatest impact on QOL followed by imbalance and then hearing loss.
Magnetic Resonance Imaging of the Brain of a Monotreme, the Short-Beaked Echidna (Tachyglossus aculeatus)
Authors: Cherupalli Sandilya , Hardman Craig D. , Bongers Andre , Ashwell Ken W.S.
Published: May 2017

We used magnetic resonance imaging to study the anatomy of cortical regions, nuclear groups, and major tracts in the brain of a monotreme, i.e., the short-beaked echidna (Tachyglossus aculeatus). Our specimens were from a collection held at the Australian Museum in Sydney and had been stored in formaldehyde solution for at least 70 years. Despite this, we were able to detect fine detail in the nuclear divisions of structures as well as in fiber tracts. In particular, we could detect the medial lemniscus as it approached the ventral posterior thalamic nucleus, subdivisions within the ventral posterior thalamic nucleus, lamination and subdivisions within the hippocampal formation, components of the olfactory pathways, and nuclei within the temporal amygdala. We were able to map the topography of subcortical white matter and relate it to cortical regions determined on the basis of physiology, as well as chemical and cytoarchitecture. As expected, dense aggregations of fibers were noted in association with the primary sensory areas of the isocortex (somatosensory, visual, and auditory) and connecting primary olfactory regions (intrabulbar anterior commissure and associated fibers). We found longitudinal fibers in the basal forebrain (medial forebrain bundle) and brainstem (corticopontine and corticospinal tracts), as well as a dense array of fibers associated with the vermal and paravermal zones of the anterior lobe of the cerebellum. We also observed previously unrecognized fiber systems, i.e., commissural connections between the paired frontal isocortical fields (dorsal Fr1), dense fibers to the retrosplenial association cortex, and prominent, paired longitudinal fiber bundles in the dorsal forebrain (longitudinal fasciculus) that intersected the dorsal anterior commissure. The connectome results are consistent with the known neuroanatomy of this monotreme and they extend our knowledge of the fiber topography within this unusual brain. Our findings demonstrate the feasibility of using this sort of imaging of archived brains to analyze the neuroanatomy of rare, endangered, and evolutionarily significant species.
Fetal Treatment 2017: The Evolution of Fetal Therapy Centers - A Joint Opinion from the International Fetal Medicine and Surgical Society (IFMSS) and the North American Fetal Therapy Network (NAFTNet)
Authors: Moon-Grady Anita J. , Baschat Ahmet , Cass Darrell , Choolani Mahesh , Copel Joshua A. , Crombleholme Timothy M. , Deprest Jan , Emery Stephen P. , Evans Mark I. , Luks Francois I. , Norton Mary E. , Ryan Greg , Tsao Kuojen , Welch Ross , Harrison Michael
Published: May 2017

More than 3 decades ago, a small group of physicians and other practitioners active in what they called “fetal treatment” authored an opinion piece outlining the current status and future challenges anticipated in the field. Many advances in maternal, neonatal, and perinatal care and diagnostic and therapeutic modalities have been made in the intervening years, yet a thoughtful reassessment of the basic tenets put forth in 1982 has not been published. The present effort will aim to provide a framework for contemporary redefinition of the field of fetal treatment, with a brief discussion of the necessary minimum expertise and systems base for the provision of different types of interventions for both the mother and fetus. Our goal will be to present an opinion that encourages the advancement of thoughtful practice, ensuring that current and future patients have realistic access to centers with a range of fetal therapies with appropriate expertise, experience, and subspecialty and institutional support while remaining focused on excellence in care, collaborative scientific discovery, and maternal autonomy and safety.
Gender-Specific Differences in Peritoneal Dialysis
Authors: Alscher Mark Dominik , Segerer Stephan , Braun Niko , Alscher M. Dominik , Latus Joerg
Published: May 2017

Background/Aims: Gender-specific differences between patients on renal replacement therapy have so far rarely been investigated. In the present study we aimed to describe gender-specific differences in a large cohort of peritoneal dialysis (PD) patients. Methods: Clinical information for all patients who started PD at our center has been collected since the start of the PD-program in 1979. We used Cox regression to examine associations between technique failure and gender. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Results: A total of 745 patients (315 women and 430 men with a median age of 57 years; IQR 43–67) started PD between 1979 and 2015 in our center. Women were significantly younger at PD start 54 (40-65) years vs. 58 (47-68) years, p<0.001. Within the last almost 15 years, more man than women started PD, but technical survival rates were significantly better in female compared to men (HR=0.662, CI 95% (0.496-0.885) P=0.005). Cardiovascular events were the main cause of death over the study period in both sexes, but decreased over time. Additionally, death due to PD-associated peritonitis decreased significantly over the three decades in both sexes. Conclusions: Our data suggest that technical survival rates were significantly better in female compared to men over three decades and death due to cardiovascular events and PD-associated peritonitis decreased significantly over the three decades in both sexes.
КЛІНІКО-ПСИХОЛОГІЧНА ХАРАКТЕРИСТИКА І КОМПЛЕКСНА ПСИХОКОРЕКЦІЯ ДЕЗАДАПТАЦІЇ У ДРУЖИН ТА МАТЕРІВ ХВОРИХ НА ПАРАНОЇДНУ ШИЗОФРЕНІЮ З ТРИВАЛИМИ ТЕРМІНАМИ ЗАХВОРЮВАННЯ, ТА ЇЇ ЕФЕКТИВНІСТЬ
Authors: Shkoda K. V.
Published: May 2017

Метою дослідження було на основі аналізу клініко-психологічних характеристик дезадаптації у дружин і матерів, хворих на параноїдну шизофренію (ПШ) з тривалими термінами захворювання, розробити комплекс психокорекційних заходів та оцінити ефективність їх впровадження. На базі Харківського обласного психоневрологічного диспансеру за період з 2012 до 2016 року за допомогою клініко-психопатологічних і психодіагностичних методів було обстежено 320 найближчих родичів хворих на ПШ чоловіків – їх матерів або дружин. Давність захворювання складала (12,7±3,4) року. Першу групу склали матері пацієнтів, які проживали в батьківській сім’ї (166 родин), другу групу – дружини психічно хворих, що мали власні сім’ї (154 родини). У результаті дослідження доведено, що дружини і матері чоловіків, хворих на ПШ з тривалими термінами захворювання, страждають від дезадаптивних станів, що проявляється у вигляді клініко-психопатологічних феноменів, особистісною та соціально-психологічною дезадаптацією. На основі отриманих даних розроблено комплекс заходів психокорекції, принциповими засадами якого є індивідуальний характер з урахуванням структури та виразності дезадаптивних змін; комплексність психокорекційних впливів; етапність психокорекції, що передбачає відповідність змісту та інтенсивності корекційних заходів етапу та рівня ураженості психіки, послідовність та спадкоємність медико-психологічних, психолого-реабілітаційних та профілактичних заходів; доступність корекційних програм для родичів хворих на ПШ, що створює передумови для широкого впровадження зазначеного комплексу в практику охорони здоров’я. Створений комплекс психокорекційних заходів, спрямований на нівеляцію проявів клініко-психологічної, особистісної і соціально-психологічної дезадаптації дружин і матерів хворих на ПШ чоловіків із тривалими термінами захворювання, виявився ефективним стосовно намічених цілей.
ПІДХОДИ ДО КОМП’ЮТЕРНОГО МОДЕЛЮВАННЯ ЕМОЦІЙНИХ СТАНІВ ПРИ ЗДІЙСНЕННІ ОПЕРАТОРСЬКОЇ ДІЯЛЬНОСТІ
Authors: Kalnysh V. V. , Shvets A. V. , Butsyk A. L.
Published: May 2017

The content-analysis of up to date literature has been carried out and on this basis the basic psychophysiological elements of different emotional status’s formation has been revealed. The approaches of this condition’s computer modeling have been developed at the realization of operator activity. The questions of computer model’s construction of emotional status formation in the human-operator have been discovered.
КЛАСИФІКАЦІЯ МЕТОДІВ РЕАБІЛІТАЦІЇ ПОСТІНСУЛЬТНИХ ХВОРИ
Authors: Azarhov O. Yu. , Zlepko S. M.
Published: May 2017

The article is devoted to complex classification of methods, which provide a rehabilitation process of postapoplectic patients damaged functions. The relationship between these methods and their clinical functional effects is showed out in this classification. Such approach allows rapidly to form the therapeutic strategy.
ПОБУДОВА СТРУКТУРИ ОНТОЛОГІЇ ДІАГНОСТИЧНОГО ТА ЛІКУВАЛЬНОГО ПРОЦЕСІВ
Authors: Krasnov V. V.
Published: May 2017

The structure of the ontology of diagnostic and medical processes is offered. The concept of an ontology orientation of medical procedural knowledge is proved. Procedural and declarative concepts are described. Three-level ontological scheme of diagnostic and medical processes is offered.