Recovery Time Constant Research Articles

Signatures of Conical Intersection Dynamics in the Time-Resolved Photoelectron Spectrum of Furan: Theoretical Modeling with an Ensemble Density Functional Theory Method.

The non-adiabatic dynamics of furan excited in the ππ* state (S2 in the Franck–Condon geometry) was studied using non-adiabatic molecular dynamics simulations in connection with an ensemble density functional method. The time-resolved photoelectron spectra were theoretically simulated in a wide range of electron binding energies that covered the valence as well as the core electrons. The dynamics of the decay (rise) of the photoelectron signal were compared with the excited-state population dynamics. It was observed that the photoelectron signal decay parameters at certain electron binding energies displayed a good correlation with the events occurring during the excited-state dynamics. Thus, the time profile of the photoelectron intensity of the K-shell electrons of oxygen (decay constant of 34 ± 3 fs) showed a reasonable correlation with the time of passage through conical intersections with the ground state (47 ± 2 fs). The ground-state recovery constant of the photoelectron signal (121 ± 30 fs) was in good agreement with the theoretically obtained excited-state lifetime (93 ± 9 fs), as well as with the experimentally estimated recovery time constant (ca. 110 fs). Hence, it is proposed to complement the traditional TRPES observations with the trXPS (or trNEXAFS) measurements to obtain more reliable estimates of the most mechanistically important events during the excited-state dynamics.

Forearm muscle mitochondrial capacity and resting oxygen uptake: Relationship to symptomatic fatigue in persons with multiple sclerosis.

BackgroundMitochondrial dysfunction has been implicated in the pathogenesis of multiple sclerosis (MS). Whether mitochondrial alterations are a function of ambulatory dysfunction or are of a non-ambulatory systemic nature is unclear.ObjectiveTo compare oxidative capacity, and rest muscle oxygen consumption (mVO2) in the upper limb of persons with multiple sclerosis (PwMS) to a control group (CON), whereby an upper limb would be comparatively independent of ambulation or deconditioning.MethodsNear infra-red spectroscopy was used to measure oxidative capacity of the wrist flexors in PwMS (n = 16) and CON (n = 13). Oxidative capacity was indicated by the time constant (TC) of mVO2 recovery following brief wrist flexion contractions. Measurements included well-being, depression, symptomatic fatigue, disability, handgrip strength, cognition, and functional endurance. Analysis was by T-tests and Pearson correlations with p ≤ 0.05. Data are mean (SD).ResultsTC of mVO2 recovery was slower in PwMS (MS = 47(14) sec, CON = 36(11) sec; p = 0.03). No significant correlations were found between oxidative capacity and any other measures. Rest mVO2 was not different between groups, but correlated with symptomatic fatigue (r = 0.694, p = 0.003) and strength (0.585, p = 0.017) in PwMS.ConclusionOxidative capacity was lower in the wrist flexors of PwMS, possibly indicating a systemic component of the disease. Within PwMS, rest mVO2 was associated with symptomatic fatigue.

Nav1.3 and FGF14 are primary determinants of the TTX-sensitive sodium current in mouse adrenal chromaffin cells.

Adrenal chromaffin cells (CCs) in rodents express rapidly inactivating, tetrodotoxin (TTX)-sensitive sodium channels. The resulting current has generally been attributed to Nav1.7, although a possible role for Nav1.3 has also been suggested. Nav channels in rat CCs rapidly inactivate via two independent pathways which differ in their time course of recovery. One subpopulation recovers with time constants similar to traditional fast inactivation and the other ∼10-fold slower, but both pathways can act within a single homogenous population of channels. Here, we use Nav1.3 KO mice to probe the properties and molecular components of Nav current in CCs. We find that the absence of Nav1.3 abolishes all Nav current in about half of CCs examined, while a small, fast inactivating Nav current is still observed in the rest. To probe possible molecular components underlying slow recovery from inactivation, we used mice null for fibroblast growth factor homology factor 14 (FGF14). In these cells, the slow component of recovery from fast inactivation is completely absent in most CCs, with no change in the time constant of fast recovery. The use dependence of Nav current reduction during trains of stimuli in WT cells is completely abolished in FGF14 KO mice, directly demonstrating a role for slow recovery from inactivation in determining Nav current availability. Our results indicate that FGF14-mediated inactivation is the major determinant defining use-dependent changes in Nav availability in CCs. These results establish that Nav1.3, like other Nav isoforms, can also partner with FGF subunits, strongly regulating Nav channel function.

The effects of tegaserod, a gastrokinetic agent, on voltage-gated K+ channels in rabbit coronary arterial smooth muscle cells.

Tegaserod, a gastroprokinetic agent, is used to treat irritable bowel syndrome. Despite its extensive clinical use, little is known about the effects of tegaserod on vascular ion channels, especially K+ channels. Therefore, we examined the effects of tegaserod on voltage-gated K+ (Kv) channels in rabbit coronary arterial smooth muscle cells using the whole-cell patch-clamp technique. Tegaserod inhibited Kv channels in a concentration-dependent manner with an IC50 value of 1.26±0.31µmol/L and Hill coefficient of 0.81±0.10. Although tegaserod had no effect on the steady-state activation curves of the Kv channels, the steady-state inactivation curve was shifted toward a more negative potential. These results suggest that tegaserod inhibits Kv channels by influencing their voltage sensors. The recovery time constant of channel inactivation was extended in the presence of tegaserod. Furthermore, application of train steps (1 and 2Hz) in the presence of tegaserod progressively increased the inhibition of Kv currents suggesting that tegaserod-induced Kv channel inhibition is use (state)-dependent. Pretreatment with a Kv1.5 subtype inhibitor suppressed the Kv current. However, additional application of tegaserod did not induce further inhibition. Pretreatment with a Kv2.1 or Kv7 inhibitor did not affect the inhibitory effect of tegaserod on Kv channels. Based on these results, we conclude that tegaserod inhibits vascular Kv channels in a concentration- and use (state)-dependent manner independent of its own functions. Furthermore, the major Kv channel target of tegaserod is the Kv1.5 subtype.

Evaluation of microchannel plate gain drops caused by high ion fluxes in time-of-flight mass spectrometry: A novel evaluation method using a multi-turn time-of-flight mass spectrometer.

Use of a two-stage microchannel plate (MCP) detector is common in time-of-flight (TOF) mass spectrometry because it shows excellent time resolution with sufficient gains. However, the gain drops significantly when the detector detects intense ion fluxes, such as matrix ions, by matrix-assisted laser desorption/ionization mass spectrometry. As a result, significant ion signals corresponding to analytes, such as proteins, are hidden, thereby hampering the mass spectral interpretation. However, details of this phenomenon have not previously been investigated using ions because of the lack of suitable measurement methods and apparatus. Thus, we herein report a novel method for controlling the TOF of two selected ions, as a function of time differences between each other using a multi-turn TOF mass spectrometer. This method involves the use of an isotope cluster of ions that fly in a figure-of-eight orbit and the extraction of an ion at a given lap number. A series of time differences (∆t) between two ions in a TOF spectrum can be generated using this method. We evaluated the time constants of gain recovery after high ion-flux detection for two sets of two-stage MCP detectors to obtain values of 1,600 and 180 μs for channel plate resistances of 500 and 71 MΩ, respectively. The obtained time constants from the gains determined at various values of ∆t were 0.48 and 0.38 fold (for 500 and 71 MΩ, respectively) of the values suggested from the channel plate resistance and capacitance.

A physically based model of the effect of recovery and clustering on recrystallization kinetics

The classical JMAK model of recrystallization kinetics has been widely used to describe the growth of randomly distributed nuclei under constant driving force. These conditions are not satisfied in many systems. The driving force for growth generally varies with time, and the nuclei are usually not uniformly distributed. In this paper, we present a physically motivated alternative model of recrystallization kinetics, which accounts for the variation of driving force due to recovery and the effect of clustering of the nuclei. The model is based on the growth kinetics of initially circular, strain free nuclei in a deformed matrix. The effect of recovery on the recrystallization kinetics is studied in terms of the parameters governing initial stored energy and the decay rate. The model predicts cessation of recrystallization when the stored energy decreases below a certain critical limit. This cessation depends on both the initial stored energy value as well as the recovery time constant. The effect of clustering of nuclei on recrystallization kinetics is analyzed by considering representative volume elements with different nuclei distributions. It is shown that recrystallization kinetics becomes slower with increased clustering. The results of this mean field model are compared to phase field simulations.

Impact of Maternal Vitamin D Receptor (VDR) Gene Polymorphisms on Spontaneous Preterm Birth (Egyptian Case-Control Study)

Diverse effects of Ba^(2+) and Co^(2+) on fura-2 fluorescence ratio signals (FR, F350/F380) were examined in cultured bovine aortic endothelial cells (BAECs). ATP (3 μM) induced FR oscillations in normal Ca^(2+)-containing solutions. Co^(2+), but not Ba^(2+), inhibited ATP-induced FR oscillations. In Ca^(2+)-free solutions, 3 μM ATP only elicited a single FR transient. When Ba^(2+) replaced Ca^(2+) in the perfusate, 3 μM ATP provoked a distinct FR transient. The maximal rate of rise of the signal was greater than seen without Ba^(2+) and the FR increased and maintained to a high steady level. When external Ca^(2+) was replaced by Co^(2+), ATP-induced FR transient oscillated with a long recovery time constant. In a survey of the single fluorescence at excitation wavelength 350 nm (F350), Co^(2+) decreased the intensity in the presence of ATP and Ca^(2+). Ba^(2+), however, increased F350 and FR as well, especially in Ca^(2+)-free solutions. The results suggest that ATP-induced Ca^(2+) fluctuation is balanced by Ca^(2+) release from internal stores and influx from external Ca^(2+). Ba2+ seems to be permeable through Ca^(2+) channels and competes with Ca^(2+) for the dye. Co^(2+) blocks Ca^(2+) channels but does not inhibit ATP-mediated Ca^(2+) release in cells.

Expression defect of the rare variant/Brugada mutation R1512W depends upon the SCN5A splice variant background and can be rescued by mexiletine and the common polymorphism H558R

ABSTRACT Background : Mutations in SCN5A that decrease Na current underlie arrhythmia syndromes such as the Brugada syndrome (BrS). SCN5A in humans has two splice variants, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077. We investigated the effect of splice variant background on loss-of-function and rescue for R1512W, a mutation reported to cause BrS. Methods and results : We made the mutation in both variants and expressed them in HEK-293 cells for voltage-clamp study. After 24 hours of transfection, the current expression level of R1512W was reduced by ~50% in both Q1077del and Q1077 compared to the wild-type (WT) channel, respectively. The activation and inactivation midpoint were not different between WT and mutant channels in both splice variant backgrounds. However, slower time constants of recovery and enhanced intermediate inactivation were observed for R1512W/Q1077 compared with WT-Q1077, while the recovery and intermediate inactivation parameters of R1512W/Q1077del were similar to WT-Q1077del. Furthermore, both mexiletine and the common polymorphism H558R restored peak sodium current (I Na) amplitude of the mutant channel by increasing the cell surface expression of SCN5A. Conclusion : These findings provide further evidence that the splice variant affects the molecular phenotype with implications for the clinical phenotype, and they provide insight into the expression defect mechanisms and potential treatment in BrS.

Greater Skeletal Muscle Oxidative Capacity Is Associated With Higher Resting Metabolic Rate: Results From the BLSA

Resting metabolic rate (RMR) tends to decline with aging. The age-trajectory of decline in RMR is similar to changes that occur in muscle mass, muscle strength and fitness. However, while the decline in these phenotypes have been related to changes of mitochondrial function and oxidative capacity, whether lower RMR is associated with poorer mitochondrial oxidative capacity is unknown. In 619 participants of the Baltimore Longitudinal Study of Aging, we analyzed the cross-sectional association between RMR (kcal/day), assessed by indirect calorimetry, and skeletal muscle maximal oxidative phosphorylation capacity, assessed as post-exercise phosphocreatine recovery time constant (tau-PCr), by phosphorous magnetic resonance spectroscopy. Linear regression models were used to evaluate the relationship between tau-PCr and RMR, adjusting for potential confounders. We found that independent of age, sex, lean body mass, muscle density and fat mass, higher RMR was significantly associated with shorter tau-PCr, indicating greater mitochondrial oxidative capacity. In conclusion, higher RMR appears to be associated with a higher mitochondrial oxidative capacity in skeletal muscle. This association may reflect a relationship between better muscle quality and greater mitochondrial health.

A Plasma Proteomic Signature of Skeletal Muscle Mitochondrial Function.

Although mitochondrial dysfunction has been implicated in aging, physical function decline, and several age-related diseases, an accessible and affordable measure of mitochondrial health is still lacking. In this study we identified the proteomic signature of muscular mitochondrial oxidative capacity in plasma. In 165 adults, we analyzed the association between concentrations of plasma proteins, measured using the SOMAscan assay, and skeletal muscle maximal oxidative phosphorylation capacity assessed as post-exercise phosphocreatine recovery time constant (τPCr) by phosphorous magnetic resonance spectroscopy. Out of 1301 proteins analyzed, we identified 87 proteins significantly associated with τPCr, adjusting for age, sex, and phosphocreatine depletion. Sixty proteins were positively correlated with better oxidative capacity, while 27 proteins were correlated with poorer capacity. Specific clusters of plasma proteins were enriched in the following pathways: homeostasis of energy metabolism, proteostasis, response to oxidative stress, and inflammation. The generalizability of these findings would benefit from replication in an independent cohort and in longitudinal analyses.

W' Reconstitution Accelerates More with Decreasing Intensity in the Heavy- versus the Moderate-Intensity Domain.

The purpose of this study was to investigate the effect of the recovery intensity domain on W' reconstitution. We used the W'BAL model as a framework and tested its predictive capabilities (W'PRED) across the different intensity domains. Twelve young men (51.7 ± 5.9 mL·kg-1·min-1) completed a ramp incremental test, three to five constant power output (PO) tests to determine critical power (CP) and W', and minimally two trials to verify the maximal lactate (La-) steady state. During four experimental trials, subjects performed two work bouts (WB1 and WB2) at P6 (i.e., PO that predicts exhaustion within 6 min) separated by a recovery interval at CP-10 W, Δgas exchange threshold (GET)-CP, GET, and 50% GET, respectively. WB1 was designed to deplete 75% W', and the recovery time varied to replenish 50% W'. WB2 was performed to exhaustion (W'ACT). W'PRED was compared with W'ACT to evaluate the accuracy of the W'BAL model. Excess postexercise oxygen consumption was calculated as the difference between the measured and the predicted oxygen uptake during recovery. W'ACT averaged 49% ± 24%, 69% ± 24%, 81% ± 28%, and 93% ± 21% for CP-10 W, ΔGET-CP, GET, and 50% GET, respectively (P = 0.002). W'PRED overestimated W'ACT in CP-10 W (34% ± 32%, P = 0.004) and underestimated W'ACT in 50% GET (24% ± 28%, P = 0.013). Excess postexercise oxygen consumption was lowest in CP-10 W (P < 0.01) and higher in GET compared with ΔGET-CP (P = 0.01). We demonstrated that W'PRED overestimated and underestimated W'ACT in the heavy- and moderate-intensity domain, respectively. Therefore, the practical applicability of a single recovery time constant, which only relies on the difference between the recovery PO and the CP, is questionable.

Cardiovascular Health and Mitochondrial Function: Testing an Association.

Although mitochondrial dysfunction appears to be a contributing factor in the pathogenesis of cardiovascular and metabolic diseases, empirical data on this association are still lacking. This study evaluated whether mitochondrial oxidative capacity, as assessed by phosphorus magnetic resonance spectroscopy, was associated with cardiovascular risk, as estimated by the Framingham Risk Score (FRS), and with a clinical history of cardiovascular disease (CVD), in community-dwelling adults. A total of 616 subjects from the Baltimore Longitudinal Study of Aging (mean age 66 years) underwent a comprehensive clinical evaluation. Mitochondrial oxidative capacity in skeletal muscle was assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy. Multivariate regression models were employed to determine the cross-sectional association of mitochondrial oxidative capacity with FRS and history of CVD. Decreased mitochondrial oxidative capacity was strongly associated with higher FRS independent of age, body composition, and physical activity. Lower oxidative capacity was also associated with a history of positive of CVD and higher number of CVD events. We speculate that the observed association could reflect the effect of an excessive production of oxidative species by dysfunctional mitochondria. Furthermore, decreased energy production could hamper the functionality of heart and vessels. In turn, a malfunctioning cardiovascular apparatus could fail to deliver the oxygen necessary for optimal mitochondrial energy production, therefore creating a vicious cycle. Longitudinal studies are necessary to ascertain the directionality of the association and the eventual presence of common pathogenetic roots. In conclusion, mitochondria could represent an important target for intervention in cardiovascular health.

Suppression of voltage-gated K+ channels by darifenacin in coronary arterial smooth muscle cells

Darifenacin, an anticholinergic agent, has been used to treat overactive bladder syndrome. Despite its extensive clinical use, there is little information about the effect of darifenacin on vascular ion channels, specifically K+ channels. This study aimed to investigate the effect of the anti-muscarinic drug darifenacin on voltage-gated K+ (Kv) channels, vascular contractility, and coronary blood flow in rabbit coronary arteries. We used the whole-cell patch-clamp technique to evaluate the effect of darifenacin on Kv channels. Darifenacin inhibited the Kv current in a concentration-dependent manner. Applying 1 μM darifenacin shifted the activation and inactivation curves toward a more positive and negative potential, respectively. Darifenacin slowed the time constants of recovery from inactivation. Furthermore, blockade of the Kv current with darifenacin was increased gradually by applying a train of pulses, indicating that darifenacin inhibited Kv currents in a use- (state)-dependent manner. The darifenacin-mediated inhibition of Kv currents was associated with the Kv1.5 subtype, not the Kv2.1 or Kv7 subtype. Applying another anti-muscarinic drug atropine or ipratropium did not affect the Kv current or change the inhibitory effect of darifenacin. Isometric organ bath experiments using isolated coronary arteries were applied to evaluate whether darifenacin-induced inhibition of the Kv channel causes vasocontraction. Darifenacin substantially induced vasocontraction. Furthermore, darifenacin caused membrane depolarization and decreased coronary blood flow. From these results, we concluded that darifenacin inhibits the Kv currents in concentration- and use- (state)-dependent manners. Inhibition of the Kv current with darifenacin occurred by shifting the steady-state activation and inactivation curves regardless of its anti-muscarinic effect.

Novel G1481V and Q1491H SCN5A Mutations Linked to Long QT Syndrome Destabilize the Nav1.5 Inactivation State

BackgroundNav1.5, which is encoded by the SCN5A gene, is the predominant voltage-gated Na+ channel in the heart. Several mutations of this gene have been identified and reported to be involved in several cardiac rhythm disorders, including type 3 long QT interval syndrome, that can cause sudden cardiac death. We analyzed the biophysical properties of 2 novel variants of the Nav1.5 channel (Q1491H and G1481V) detected in 5- and 12-week-old infants diagnosed with a prolonged QT interval. MethodsThe Nav1.5 wild-type and the Q1491H and G1481V mutant channels were reproduced in vitro. Wild-type or mutant channels were cotransfected in human embryonic kidney (HEK) 293 cells with the beta 1 regulatory subunit. Na+ currents were recorded using the whole-cell configuration of the patch-clamp technique. ResultsThe Q1491H mutant channel exhibited a lower current density, a persistent Na+ current, an enhanced window current due to a +20-mV shift of steady-state inactivation, a +10-mV shift of steady-state activation, a faster onset of slow inactivation, and a recovery from fast inactivation with fast and slow time constants of recovery. The G1481V mutant channel exhibited an increase in current density and a +7-mV shift of steady-state inactivation. The observed defects are characteristic of gain-of-function mutations typical of type 3 long QT interval syndrome. ConclusionsThe 5- and 12-week-old infants displayed prolonged QT intervals. Our analyses of the Q1491H and G1481V mutations correlated with the clinical diagnosis. The observed biophysical dysfunctions associated with both mutations were most likely responsible for the sudden deaths of the 2 infants.

Inhibition by Imipramine of the Voltage-Dependent K+ Channel in Rabbit Coronary Arterial Smooth Muscle Cells.

Imipramine, a tricyclic antidepressant, is used in the treatment of depressive disorders. However, the effect of imipramine on vascular ion channels is unclear. Therefore, using a patch-clamp technique we examined the effect of imipramine on voltage-dependent K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells. Kv channels were inhibited by imipramine in a concentration-dependent manner, with an IC50 value of 5.55 ± 1.24 µM and a Hill coefficient of 0.73 ± 0.1. Application of imipramine shifted the steady-state activation curve in the positive direction, indicating that imipramine-induced inhibition of Kv channels was mediated by influencing the voltage sensors of the channels. The recovery time constants from Kv-channel inactivation were increased in the presence of imipramine. Furthermore, the application of train pulses (of 1 or 2 Hz) progressively augmented the imipramine-induced inhibition of Kv channels, suggesting that the inhibitory effect of imipramine is use (state) dependent. The magnitude of Kv current inhibition by imipramine was similar during the first, second, and third depolarizing pulses. These results indicate that imipramine-induced inhibition of Kv channels mainly occurs in the closed state. The imipramine-mediated inhibition of Kv channels was associated with the Kv1.5 channel, not the Kv2.1 or Kv7 channel. Inhibition of Kv channels by imipramine caused vasoconstriction. From these results, we conclude that imipramine inhibits vascular Kv channels in a concentration- and use (closed-state)-dependent manner by changing their gating properties regardless of its own function.

TARPs Modulate Receptor-Mediated Paired-Pulse Depression and Recovery from Desensitization.

Transmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary AMPA receptor subunits that play a key role in receptor trafficking and in modulating receptor gating. The ability of TARPs to slow both deactivation and desensitization is isoform specific. However, TARP isoform-specific modulation of receptor properties remains uncharacterized. Here, we compare the isoform-specific effects of γ-2, γ-3, γ-4, and γ-8 TARPs on recovery from desensitization and responses to pairs of brief applications of glutamate. All four isoforms were able to reduce receptor-mediated paired-pulse depression and significantly speed recovery from desensitization in an isoform-specific manner. In the presence of TARPs, recovery time courses were observed to contain two components, fast and slow. The proportion of fast and slow components was determined by the TARP isoform. The time constant of recovery was also altered by the duration of glutamate application. When studies with TARP chimeras were performed, TARP extracellular loops were found to play a vital role in TARP modulation of recovery. Thus, isoform-specific differences in TARP modulation of recovery from desensitization influence receptor responses to repeated brief applications of glutamate, and these differences may impact frequency-dependent synaptic signaling in the mammalian central nervous system.SIGNIFICANCE STATEMENT AMPA receptors are major determinants of excitatory synaptic strength. The channel kinetics of AMPA receptors contribute to the kinetics of synaptic transmission. Transmembrane AMPA receptor regulatory proteins (TARPs) auxiliary subunits can modulate the decay kinetics of AMPA receptors. However, whether TARP isoforms specifically modulate receptor recovery is unclear. Here, we investigated the recovery kinetics of AMPA receptors by expressing various TARP isoforms and chimeras. We observed that the TARP isoforms and duration of glutamate application uniquely modulate time constants and the proportion of fast and slow components through a previously unidentified TARP domain. Given the impact of recovery kinetics on receptor responses to repetitive stimulation such as synaptic transmission, this work will be of great interest in the field of excitatory synaptic transmission research.

Prediction of the Functional Status of the Cochlear Nerve in Individual Cochlear Implant Users Using Machine Learning and Electrophysiological Measures.

This study aimed to create an objective predictive model for assessing the functional status of the cochlear nerve (CN) in individual cochlear implant (CI) users. Study participants included 23 children with cochlear nerve deficiency (CND), 29 children with normal-sized CNs (NSCNs), and 20 adults with various etiologies of hearing loss. Eight participants were bilateral CI users and were tested in both ears. As a result, a total of 80 ears were tested in this study. All participants used Cochlear Nucleus CIs in their test ears. For each participant, the CN refractory recovery function and input/output (I/O) function were measured using electrophysiological measures of the electrically evoked compound action potential (eCAP) at three electrode sites across the electrode array. Refractory recovery time constants were estimated using statistical modeling with an exponential decay function. Slopes of I/O functions were estimated using linear regression. The eCAP parameters used as input variables in the predictive model were absolute refractory recovery time estimated based on the refractory recovery function, eCAP threshold, slope of the eCAP I/O function, and negative-peak (i.e., N1) latency. The output variable of the predictive model was CN index, an indicator for the functional status of the CN. Predictive models were created by performing linear regression, support vector machine regression, and logistic regression with eCAP parameters from children with CND and the children with NSCNs. One-way analysis of variance with post hoc analysis with Tukey's honest significant difference criterion was used to compare study variables among study groups. All three machine learning algorithms created two distinct distributions of CN indices for children with CND and children with NSCNs. Variations in CN index when calculated using different machine learning techniques were observed for adult CI users. Regardless of these variations, CN indices calculated using all three techniques in adult CI users were significantly correlated with Consonant-Nucleus-Consonant word and AzBio sentence scores measured in quiet. The five oldest CI users had smaller CN indices than the five youngest CI users in this study. The functional status of the CN for individual CI users was estimated by our newly developed analytical models. Model predictions of CN function for individual adult CI users were positively and significantly correlated with speech perception performance. The models presented in this study may be useful for understanding and/or predicting CI outcomes for individual patients.

Statin Therapy Does Not Limit Improvements In Mitochondrial Function And Cardiorespiratory Fitness Following Moderate Exercise

INTRODUCTION: Statin medications are widely used to reduce major cardiovascular risk factors and events, but have also been reported to reduce cardiorespiratory and mitochondrial adaptations expected with aerobic exercise training. The current study evaluated the influence of statin therapy on aerobic exercise training adaptations in older adults. METHODS: Twenty-eight healthy, sedentary older adults (67±5 yrs old, BMI=30±5, mean±SD, 5 males) participated in a 12-week randomized graded treadmill walking intervention (EX) with roughly half the group on statin therapy (+statin). 31P MRS was used to quantify oxidative capacity of the plantar flexor muscles (3T MRI, 51.7MHz, TR=3s); a monoexponential model was used to fit the time constant of phosphocreatine recovery following acute plantar flexion. Peak oxygen consumption (VO2 peak) was measured during a modified Balke exercise stress test. Repeated measures ANOVA was used to assess changes in muscle oxidative capacity and VO2 peak between groups with significance at p<0.05. RESULTS: Prior to the exercise intervention, PCr time constant (tau, s) was significantly prolonged in statin users (+statin 42.2±10.5s; -statin =34.1±9.9s; p=0.039). Following exercise training, the time constant was reduced by 27% (Pre: 40.3±29.6s; Post: 29.6±10.4s) for EX compared to CON (Pre: 35.5±6.3s to 36.4±9.0s), p=0.001, n=27. There was no significant effect of statin therapy with a 28.0% improvement for EX+statin compared to a 25.3% for EX-statin. VO2 peak increased 11% following EX (Pre:18.8±2.8 ml/kg/min, Post: 20.1±3.5 ml/kg/min) compared to CON (Pre: 21.8±3.7, Post: 20.8±3.6 ml/kg/min), p=0.001, n=21 with no effect of statin therapy. CONCLUSION: Moderate exercise training in older adults on a low dose statin resulted in typical increases in aerobic fitness. These results are encouraging for the majority of older adults as 50% or more are likely to be prescribed a statin for reduction in cardiovascular event risk or prevention of metabolic syndrome. Supported by NIH AG042041.

Multinuclear MRS at 7T Uncovers Exercise Driven Differences in Skeletal Muscle Energy Metabolism Between Young and Seniors.

Purpose: Aging is associated with changes in muscle energy metabolism. Proton (1H) and phosphorous (31P) magnetic resonance spectroscopy (MRS) has been successfully applied for non-invasive investigation of skeletal muscle metabolism. The aim of this study was to detect differences in adenosine triphosphate (ATP) production in the aging muscle by 31P-MRS and to identify potential changes associated with buffer capacity of muscle carnosine by 1H-MRS.Methods: Fifteen young and nineteen elderly volunteers were examined. 1H and 31P-MRS spectra were acquired at high field (7T). The investigation included carnosine quantification using 1H-MRS and resting and dynamic 31P-MRS, both including saturation transfer measurements of phosphocreatine (PCr), and inorganic phosphate (Pi)-to-ATP metabolic fluxes.Results: Elderly volunteers had higher time constant of PCr recovery (τPCr) in comparison to the young volunteers. Exercise was connected with significant decrease in PCr-to-ATP flux in both groups. Moreover, PCr-to-ATP flux was significantly higher in young compared to elderly both at rest and during exercise. Similarly, an increment of Pi-to-ATP flux with exercise was found in both groups but the intergroup difference was only observed during exercise. Elderly had lower muscle carnosine concentration and lower postexercise pH. A strong increase in phosphomonoester (PME) concentration was observed with exercise in elderly, and a faster Pi:PCr kinetics was found in young volunteers compared to elderly during the recovery period.Conclusion: Observations of a massive increment of PME concentration together with high Pi-to-ATP flux during exercise in seniors refer to decreased ability of the muscle to meet the metabolic requirements of exercise and thus a limited ability of seniors to effectively support the exercise load.

Skeletal Muscle Mitochondrial Dysfunction Is Present in Patients with CKD before Initiation of Maintenance Hemodialysis.

Patients with CKD suffer from frailty and sarcopenia, which is associated with higher morbidity and mortality. Skeletal muscle mitochondria are important for physical function and could be a target to prevent frailty and sarcopenia. In this study, we tested the hypothesis that mitochondrial dysfunction is associated with the severity of CKD. We also evaluated the interaction between mitochondrial function and coexisting comorbidities, such as impaired physical performance, intermuscular adipose tissue infiltration, inflammation, and oxidative stress. Sixty-three participants were studied, including controls (n=21), patients with CKD not on maintenance hemodialysis (CKD 3-5; n=20), and patients on maintenance hemodialysis (n=22). We evaluated in vivo knee extensors mitochondrial function using 31P magnetic resonance spectroscopy to obtain the phosphocreatine recovery time constant, a measure of mitochondrial function. We measured physical performance using the 6-minute walk test, intermuscular adipose tissue infiltration with magnetic resonance imaging, and markers of inflammation and oxidative stress in plasma. In skeletal muscle biopsies from a select number of patients on maintenance hemodialysis, we also measured markers of mitochondrial dynamics (fusion and fission). We found a prolonged phosphocreatine recovery constant in patients on maintenance hemodialysis (53.3 [43.4-70.1] seconds, median [interquartile range]) and patients with CKD not on maintenance hemodialysis (41.5 [35.4-49.1] seconds) compared with controls (38.9 [32.5-46.0] seconds; P=0.001 among groups). Mitochondrial dysfunction was associated with poor physical performance (r=0.62; P=0.001), greater intermuscular adipose tissue (r=0.44; P=0.001), and increased markers of inflammation and oxidative stress (r=0.60; P=0.001). We found mitochondrial fragmentation and increased content of dynamin-related protein 1, a marker of mitochondrial fission, in skeletal muscles from patients on maintenance hemodialysis (0.86 [0.48-1.35] arbitrary units (A.U.), median [interquartile range]) compared with controls (0.60 [0.24-0.75] A.U.). Mitochondrial dysfunction is due to multifactorial etiologies and presents prior to the initiation of maintenance hemodialysis, including in patients with CKD stages 3-5.