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In endotherms, such as mammals and birds, internal organs can specialise to function within a narrow thermal range. Consequently, these organs should become more sensitive to changes in body temperature. Yet, organs at the periphery of the body still experience considerable fluctuations in temperature, which could select for lower thermal sensitivity. We hypothesised that the performance of soleus muscle taken from the leg would depend less on temperature than would the performance of diaphragm muscle taken from the body core. Soleus and diaphragm muscles were isolated from mice and subjected to isometric and work-loop studies to analyse mechanical performance at temperatures between 15 and 40 °C. Across this thermal range, soleus muscle took longer to generate isometric force and longer to relax, and tended to produce greater normalised maximal force (stress) than did diaphragm muscle. The time required to produce half of maximal force during isometric tetanus and the time required to relax half of maximal force were both more sensitive to temperature in soleus than they were in diaphragm. However, thermal sensitivities of maximal force during isometric tetani were similar for both muscles. Consistent with our hypothesis, power output (the product of speed and force) was greater in magnitude and more thermally sensitive in diaphragm than it was in soleus. Our findings, when combined with previous observations of muscles from regionally endothermic fish, suggest that endothermy influences the thermal sensitivities of power output in core and peripheral muscles.

The present study aimed to investigate corticospinal excitability changes during muscle relaxation with a tracking task. The motor-evoked potential, which was elicited from the flexor carpi radialis (agonist) and extensor carpi radialis (antagonist) muscles, was analyzed in terms of both the relaxation velocity and phase. Our results suggest that increasing corticospinal excitability in the antagonist muscle plays an important role in controlling the relaxation of the agonist muscle during gradual relaxation with a tracking task.

Objectives/hypothesis: This study aimed to evaluate changes in obstruction site in obstructive sleep apnea (OSA) patients according to sleep position., Study Design: Prospective case series., Methods: Eighty-five patients who had undergone level 1 sleep study and drug-induced sleep endoscopy in the supine and lateral positions were included. Obstruction sites were classified as soft palate (SP), tongue base (TB), lateral wall (LW), and larynx (LX). Subgroup analysis was performed according to lateral apnea-hypopnea index (AHI): those with an AHI of ≥ 10 (lateral obstructors, LO) and those with an AHI of < 10 (lateral nonobstructors, LNO)., Results: Prevalence in obstruction site of SP, TB, and LX decreased significantly after change from supine to lateral position (P < 0.05). However, the prevalence of LW obstruction was not affected by position change. LW collapse in moderate OSA decreased (from 66.7% to 35.9%) after change to lateral sleep, whereas it persisted in severe OSA patients (81.6%-89.5%). In the lateral position, persistent obstruction at the LW was observed more frequently in the LO group compared to the LNO group (83.3% vs. 33.3%)., Conclusion: When sleep posture is changed from supine to lateral, obstruction due to structures such as tongue base and larynx improves dramatically. Obstruction in lateral position is mostly due to obstruction at the oropharyngeal LWs. Therefore, position dependency is mostly determined by LW collapsibility. Evaluating the changes of the upper airway according to sleep position can further characterize the upper airway collapsibility and can be used for tailored treatment planning., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: The purpose of this study was to determine which kinematic measure most consistently determined onset and cessation of the flexion-relaxation response., Methods: The study was a cross-sectional design in a laboratory setting in which 20 asymptomatic university-aged (19.8-33.3 years old) participants were tested. Muscle activation was measured for the lumbar erector spinae, and 3-dimensional motion was recorded. Flexion-relaxation onset and cessation occurrences were determined for 10 standing maximum voluntary flexion trials. The lumbar and trunk angles at both events were expressed as unnormalized (°) and normalized (%Max: percentage of maximum voluntary flexion) measures. Intraclass correlation coefficients and coefficients of variation were calculated to determine within- and between-participant reliability, respectively., Results: Mean (SD) unnormalized flexion-relaxation angles ranged from 46.28° (11.63) (lumbar onset) to 108.10° (12.26) (trunk cessation), whereas normalized angles ranged from 71.31%Max (16.44) (trunk onset) to 94.83%Max (lumbar cessation). Intraclass correlation coefficients ranged from 0.905 (normalized lumbar, left side, onset) to 0.995 (unnormalized lumbar, both sides, cessation). Coefficients of variation ranged from 3.56% (normalized lumbar, right side, cessation) to 26.02% (unnormalized trunk, left side, onset)., Conclusions: The data suggest that, for asymptomatic individuals, unnormalized and normalized lumbar kinematics most consistently characterized flexion-relaxation angles within and between participants, respectively. Lumbar measures may be preferential when the flexion-relaxation response is investigated in future clinical and biomechanical studies., (Copyright © 2015 National University of Health Sciences. Published by Elsevier Inc. All rights reserved.)

We constructed an arm holder for muscle exercise from a forearm-shaped plastic shell and magnetic resonance (MR) imaging position markers and determined the echo time (39 ms) for T₂-weighted spin-echo MR imaging from T₂values of the exercised (50 ms) and resting (32 ms) muscle at 0.2 tesla. The smallest detectable muscle was the extensor digiti minimi muscle (cross-sectional area 25 mm²). This combination could be useful to monitor finger exercise in patients undergoing physical therapy.

Objectives: Beside traditional dysphagia therapy, neuromuscular electrical stimulation (NMES) has been proposed to treat patients with dysphagia. Considering the complexity of the nerve-muscle interaction during swallowing, the underlying physiology of NMES remains unclear. Here, we addressed the question of whether NMES can modify upper esophageal sphincter (UES) dynamics., Methods: In a prospective study, 26 healthy volunteers performed water swallows with and without NMES. The stimulus was applied in a participant- and operator-initiated stimulation above, near, and below the motor threshold. Swallowing parameters were measured using high-resolution manometry., Results: The UES relaxation time was found to be extended by 10%, indicating a modification in UES dynamics., Conclusions: The chosen NMES paradigm influenced the involuntary swallowing phase by extending relaxation time, providing more time for bolus passage into the esophagus. Future studies will have to evaluate if this effect can be found in patients with dysphagia and whether it is beneficial for treatment., (© The Author(s) 2014.)

Pulse transit time (PTT), which refers to the time it takes a pulse wave to travel between two arterial sites is a promising index for cuff-less blood pressure (BP) estimation, as well as non-invasive assessment of arterial functions. However, it has not been investigated whether PTTs measured from ECG and different wavelength PPG are equally affected by the arterial status. Furthermore, comparison between the changes of different PTTs can provide enlightenment on the hardware implementation of the PTT-based BP estimation method. This work mainly studied the changes of PTTs calculated from electrocardiogram (ECG) and multi-wavelength photoplethysmogram (PPG) after exerting cuff pressure on the upper arm. A four-channel PPG acquisition system was developed to collect the multi-wavelength PPG signals of red, yellow, green and blue light at the fingertip simultaneously. Ten subjects participated in the experiment and their PTTs measured from different PPG and ECG signals before and after exerting cuff pressure were compared. This study found that within one minute after the four-minute cuff inflation and deflation process, the PTT measured from ECG and yellow PPG experienced a significant increase (p<;0.05) while the PTT from ECG and blue PPG had no statistical difference (p>0.9) compared with that before exerting cuff pressure. This indicates that PTTs calculated from different wavelength PPG have different recoverability from smooth muscle relaxation. Another interesting finding is that the PTT calculated from ECG and yellow PPG had a strong correlation (|r|>0.7) with the time difference between yellow PPG and other PPG signals, which implies the potential of the time difference between yellow PPG and other PPGs as a complementary to PTT-based model for blood pressure estimation.

We have previously demonstrated that menthol reduces murine gastric tone in part through a neural mechanism, involving adrenergic pathways and reduction of ongoing release of acetylcholine from enteric nerves. In the present study we aimed to verify whether the gastric relaxation to menthol may be triggered by interaction with neural receptors or ionic channels proteins, such as transient receptor potential (TRP)-melastatin8 (TRPM8), TRP-ankyrin 1 (TRPA1), 5-hydroxytriptamine 3 (5-HT3) receptor or cholinergic nicotinic receptors. Spontaneous mechanical activity was detected in vitro as changes in intraluminal pressure from isolated mouse stomach. Menthol (0.3-30 mM) induced gastric relaxation which was not affected by 5-benzyloxytryptamine, a TRPM8 receptor antagonist, HC030031, a TRPA1 channel blocker. In addition, allylisothiocyanate, a TRPA1 agonist, but not (2S,5R)-2-Isopropyl-N-(4-methoxyphenyl)-5-methylcyclohexanecarboximide, a selective TRPM8 agonist, induced gastric relaxation. Genic expression of TRPA1, but not of TRPM8, was revealed in mouse stomach. Indeed, menthol-induced gastric relaxation was significantly reduced by hexamethonium, cholinergic nicotinic receptor antagonist. Menthol, at concentrations that failed to affect gastric tone, reduced the contraction induced by dimethylphenylpiperazinium, nicotinic receptor agonist. The joint application of hexamethonium and atropine, muscarinc receptor antagonist, or hexamethonium and phentholamine, α-adrenergic receptor antagonist, did not produce any additive reduction of the relaxant response to menthol. Lastly, ondansetron, a 5-HT3 receptor antagonist, was ineffective. In conclusion, our study suggests that nicotinic receptors, but not TRP and 5-HT3 receptors, are molecular targets for menthol inducing murine gastric relaxation, ultimately due to the reduction of acetylcholine release from enteric nerves., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Study Objective: To determine if prewarming of the i-gel (Intersurgical, Wokingham, United Kingdom) improves insertion and ventilation efficacy with muscle relaxation in patients undergoing elective surgery., Design: Clinical randomized study., Setting: Operating room., Patients: Sixty-eight adult patients scheduled for elective surgery under general anesthesia with American Society of Anesthesiologists physical status 1-3., Interventions: The i-gel was warmed to 42°C for 30 minutes before insertion (W group; 34 patients) or kept at room temperature (approximately 23°C) (C group; 34 patients)., Measurements: The number of attempts for a successful insertion and the sealing pressure and leak volume 30 seconds and 30 minutes after initiating mechanical ventilation., Main Results: The total insertion attempts were 1 (W group, 31 cases; C group, 24 cases) and 2 (W group, 3 cases; C group, 10 cases), which was significant (P = .001). Sealing pressure was significantly higher in the W group than the C group (W group, 21.8 ± 3.7 cm H2O; C group, 18.5 ± 3.4 cm H2O; P = .001). Leak volume was significantly smaller after 30 seconds in the W group than the C group (P = .002), but not after 30 minutes (P = .69)., Conclusions: Prewarming the i-gel to 42°C demonstrated a higher successful ventilation initiation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: ATP and nitric oxide (NO) are released from enteric inhibitory motor neurones and are responsible for colonic smooth muscle relaxation. However, how frequency of neural stimulation affects this cotransmission process and the post-junctional responses has not been systematically characterized in the human colon., Methods: The dynamics of inhibitory cotransmission were studied using different protocols of electrical field stimulation (EFS) to characterize the inhibitory junction potentials (IJP) and the corresponding relaxation in colonic strips obtained from 36 patients., Results: Single pulses elicited a fast IJP (IJPf(MAX) = -27.6 ± 1.6 mV), sensitive to the P2Y1 antagonist MRS2500 1 μm, that ran down with frequency increase leaving a residual hyperpolarization at high frequencies (IJPf∞ = -3.7 ± 0.6 mV). Accordingly, low frequencies of EFS caused purinergic transient relaxations that cannot be maintained at high frequencies. Addition of the P2Y1 agonist MRS2365 10 μm during the purinergic rundown did not cause any hyperpolarization. Protein kinase C (PKC), a putative P2Y1 desensitizator, was able to reduce the amplitude of the IJPf when activated, but the rundown was not modified by PKC inhibitors. Frequencies higher than 0.60 ± 0.15 Hz were needed to evoke a sustained nitrergic hyperpolarization that progressively increased reaching IJPs∞ = -13 ± 0.4 mV at high frequencies and leading to a sustained inhibition of spontaneous motility., Conclusion: Changes in frequency of stimulation possibly mimicking neuronal firing will post-junctionally determine purinergic vs. nitrergic responses underlying different functional roles. NO will be responsible for sustained relaxations needed in physiological processes such as storage, while purinergic neurotransmission evoking sharp transient relaxations will be dominant in processes such as propulsion., (© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Introduction and Hypothesis: Effects of tadalafil, a phosphodiesterase type 5 inhibitor, on the urethral continence reflex induced by sneezing were investigated., Methods: The amplitude of urethral pressure responses during sneezing (A-URS) and urethral baseline pressure (UBP) were measured in female rats using a microtransducer-tipped catheter. Sneeze leak-point pressure (S-LPP), defined as the lowest amount of pressure required to induce fluid leakage from the urethral orifice during sneezing, was measured in rats with stress urinary incontinence (SUI) induced by vaginal distension. Values were determined before and after tadalafil administration., Results: Tadalafil dose dependently and significantly decreased A-URS and S-LPP. At the highest dose tested (6.0 mg/kg), A-URS and S-LPP decreased from 49.7 to 32.3 and from 63.9 to 44.2 cmH2O, respectively, whereas UBP did not significantly change., Conclusions: Tadalafil attenuated the sneeze-induced urethral continence reflex by relaxing the striated muscles of the external urethral sphincter.

Background: The hamstring injury mechanism was assessed by investigating the exercise-related metabolic activity characteristics of the hamstring muscles using a muscle functional MRI (mfMRI) protocol., Methods: 27 healthy male football players and 27 football players with a history of hamstring injuries (recovered and playing fully) underwent standardised mfMR Imaging. The mfMRI protocol consisted of a resting scan, a strenuous bilateral eccentric hamstring exercise and a postexercise scan. The exercise-related T2 increase or the signal intensity shift between both scans was used to detect differences in metabolic activation characteristics (1) between the different hamstring muscle bellies and (2) between the injury group and the control group., Results: A more symmetrical muscle recruitment pattern corresponding to a less economic hamstring muscle activation was demonstrated in the formerly injured group (p<0.05). The injured group also demonstrated a significantly lower strength endurance capacity during the eccentric hamstring exercise., Conclusions: These findings suggest that the vulnerability of the hamstring muscles to football-related injury is related to the complexity and close coherence in the synergistic muscle recruitment of the biceps femoris and the semitendinosus. Discrete differences in neuromuscular coordination and activity distribution, with the biceps femoris partly having to compensate for the lack of endurance capacity of the semitendinosus, probably increase the hamstring injury risk., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To determine the presence of calcium activated chloride channels anoctamin 1 (ANO1) and 2 (ANO2) in human and murine uterine smooth muscle (MUSM) and evaluate the physiologic role for these ion channels in murine myometrial contractility., Study Design: We performed reverse transcription polymerase chain reaction to determine whether ANO1 and 2 are expressed in human and murine uterine tissue to validate the study of this protein in mouse models. Immunohistochemical staining of ANO1 and 2 was then performed to determine protein expression in murine myometrial tissue. The function of ANO1 and 2 in murine uterine tissue was evaluated using electrophysiologic studies, organ bath, and calcium flux experiments., Results: ANO1 and 2 are expressed in human and MUSM cells. Functional studies show that selective antagonism of these channels promotes relaxation of spontaneous MUSM contractions. Blockade of ANO1 and 2 inhibits both agonist-induced and spontaneous transient inward currents and abolishes G-protein coupled receptor (oxytocin) mediated elevations in intracellular calcium., Conclusion: The calcium activated chloride channels ANO1 and 2 are present in human and murine myometrial tissue and may provide novel potential therapeutic targets to achieve effective tocolysis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In this study the effect of muscle fatigue on the cervical spine flexion-relaxation response was studied. Twenty healthy participants (10 males and 10 females) were recruited for data collection. The Sorenson protocol was utilized to induce neck muscle fatigue. Surface electromyography and optical motion capture systems were used to measure neck muscle activation and head-neck posture, respectively. A post-fatigue reduction in the Flexion-Relaxation Ratio (FRR) and higher FRR for females compared to males were observed. A post-fatigue decrease was also observed in the onset and offset angles resulting in an expansion of the myoelectric silence period. Gender had no effect on the onset and offset angles of the silence period. Post-fatigue shift in the onset and offset angles and the expansion of the silence period indicate an increased contribution by the passive viscoelastic tissues in stabilizing the cervical spine under fatigued condition., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Relaxation of the esophagogastric junction (EGJ) is now evaluated calculating 4-second integrated relaxation pressure (4-s IRP) by high resolution manometry (HREPT). Solid-state catheters have been used to define abnormal values. Our aim was to evaluate 4-s IRP in esophageal achalasia using HREPT with perfused catheters., Methods: From June 2009 to June 2013, 936 HREPT studies have been performed in our unit. Of these, 194 patients having treated achalasia were excluded. Control group was constituted by 695 patients without achalasia, and 47 patients with untreated achalasia constituted the study group. HREPT was performed with water-perfused catheters. To establish the cut-off value for 4-s IRP that better discriminate patients with achalasia from all other patients, a receiver operating characteristic (ROC) analysis was performed., Key Results: Twenty three of 47 achalasia patients (49%) showed a 4-s IRP under 15 mmHg; and seven (15%) had a value under modified Chicago criteria. A cut-off value for 4-s IRP of 6.5 mmHg, calculated by ROC analysis, highly discriminates achalasia from the rest of the patients and especially from scleroderma patients (area under the curve: 0.997, 95% CI: 0.995-1.000; p < 0.001)., Conclusions & Inferences: Cut-off values for 4-s IRP defined using HREPT with solid-state catheters are not adequate for diagnosing esophageal achalasia with water-perfused systems. A lower value, i.e., 6.5 mmHg, is suggested for this equipment. The diagnostic criteria of esophageal achalasia should be modified for HREPT performed with water-perfused systems., (© 2014 John Wiley & Sons Ltd.)

Background: Cinaciguat (BAY 58-2667), an NO- and heme-independent sGC activator, was shown to be more effective when the heme-group of sGC is oxidized in vascular tissue. In apo-sGC mice (sGCβ1 (His105Phe) knockin) both sGC isoforms (sGCα1 β1 and sGCα2 β1 ) are heme-deficient and can no longer be activated by NO; these mice, showing decreased gastrointestinal nitrergic relaxation and decreased gastric emptying, can be considered as a model to study the consequence of heme-oxidation in sGC. Our aim was to compare the influence of cinaciguat, on in vitro muscle tone of gastrointestinal tissues, and on gastric emptying in WT and apo-sGC mice., Methods: Gastrointestinal smooth muscle strips were mounted in organ baths for isometric force recording and cGMP levels were determined by enzyme immunoassay. Protein levels of sGC subunits were assessed by immunoblotting. Gastric emptying was determined by phenol red recovery., Key Results: Although protein levels of the sGC subunits were lower in gastrointestinal tissues of apo-sGC mice, cinaciguat induced concentration-dependent relaxations and increased cGMP levels in apo-sGC fundus and colon to a similar or greater extent than in WT mice. The sGC inhibitor ODQ increased cinaciguat-induced relaxations and cGMP levels in WT fundus and colon. In apo-sGC antrum, pylorus and jejunum, cinaciguat was not able to induce relaxations. Cinaciguat did not improve delayed gastric emptying in apo-sGC mice., Conclusions & Inferences: Cinaciguat relaxes the fundus and colon efficiently when sGC is in the heme-free condition; the non-effect of cinaciguat in pylorus explains its inability to improve the delayed gastric emptying in apo-sGC mice., (© 2014 John Wiley & Sons Ltd.)

Background: Cirrhosis, associated with a host of hemodynamic abnormalities, could affect the gastrointestinal (GI) tract motility. On the other hand, the nonadrenergic noncholinergic (NANC) neurotransmission has been shown to play a pivotal role in GI tract motility and has been linked with release of nitric oxide (NO) on electrical stimulation. In this study, we investigated the effect of biliary cirrhosis on the neurogenic relaxation of rat gastric fundus and anococcygeus muscle and also the possible role of nitric oxide system in this manner., Methods: Isolated gastric fundus and anococcygeus strips of sham-operated and biliary cirrhotic (4 weeks after bile duct ligation) rats were mounted under tension in a standard organ bath. Electrical stimulation was applied to obtain NANC-mediated relaxations in precontracted gastric fundus and anococcygeus muscle. The neurogenic relaxations were examined in the presence of different doses of NO synthase inhibitor, N (w)-Nitro-L-Arginine Methyl Ester (L-NAME). The concentration-dependent relaxant responses to the NO donor sodium nitroprusside were also evaluated., Results: The neurogenic relaxation of both gastric fundus and anococcygeus muscle was significantly (P < 0.001) increased in cirrhotic animals. L-NAME (0.03-1,000 µM) inhibited relaxations in both groups in a dose-dependent manner (P < 0.001), but cirrhotic groups were more resistant to the inhibitory effects of L-NAME (P < 0.01). Sodium nitroprusside-mediated relaxations were similar in two groups., Conclusions: This study for the first time demonstrated that cirrhosis increases the NO-mediated neurogenic relaxation of both rat gastric fundus and anococcygeus muscle, suggesting a crucial role for the neurogenic NO in the pathophysiology of disturbed GI motility in cirrhosis.

Recent studies have suggested that hydrogen sulfide (H2S), an important endogenous signaling gaseous molecule, participates in relaxation of smooth muscle. Nevertheless, the mechanism of this relaxation effect on respiratory system is still unclear. The present study aims to investigate the physiological function as well as cellular mechanism of H2S in tracheal smooth muscle. Application of the H2S donor, sodium hydrosulphide (NaHS) and the precursor of H2S, l-cysteine (l-Cys) induced mouse tracheal smooth muscle (TSM) relaxation in an epithelium-independent manner. The relaxation of TSM induced by NaHS was abrogated by iberiotoxin (IbTX), the large conductance calcium activated potassium channel (BKCa) blocker. In primary cultured mouse TSM cells, NaHS remarkably increased potassium outward currents in whole-cell patch clamp, hyperpolarized TSM cells and inhibited the calcium influx. All of these effects were significantly blocked by IbTX. Consistent with the results in vitro, administration of NaHS in vivo also reduced airway hyperresponsiveness in Ovalbumin (OVA)-challenged asthmatic mice. Our present study indicates that NaHS can induce mouse TSM relaxation by activating BKCa. These observations reveal the physiological function of H2S in airway, which provides a promising pharmacological target for the treatment of asthma and other respiratory diseases associated with over-contraction of TSM., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Anismus or non-relaxing puborectalis muscle (PRM), detectable with anal/vaginal ultrasound (US), is a cause of obstructed defecation (OD) and may be treated with biofeedback (BFB). Many patients with anismus are anxious and/or depressed. The aim of this prospective study was to evaluate the outcome of the novel procedure psycho-echo-BFB in patients with anismus and psychological disorders., Methods: Patients presenting at our unit with anismus and psychological disorders between January 2009 and December 2013, and not responding to conventional conservative treatment, were enrolled in the study. All underwent four sessions of psycho-echo-BFB, carried out by two psychologists and a coloproctologist, consisting of guided imagery, relaxation techniques and anal/vaginal US-assisted BFB. A validated score for OD was used, and PRM relaxation on straining measured before and after the treatment. PRM relaxation was also measured in a control group of 7 patients with normal bowel habits., Results: Ten patients (8 females, median age 47 years, range 26-72 years) underwent psycho-echo-BFB. The OD score, evaluated prior to and at a median of 25 months (range 1-52 months) after the treatment, improved in 7 out of 10 patients, from 13.5 ± 1.2 to 9.6 ± 2.2 (mean ± standard error of the mean (SEM)), p = 0.06. At the end of the last session, PRM relaxed on straining in all cases, from 0 to 7.1 ± 1.1 mm, i.e., physiological values, not statistically different from those of controls (6.6 ± 1.5 mm). Two patients reported were cured, 3 improved and 5, all of whom had undergone prior anorectal surgery, unchanged. No side effects were reported., Conclusions: Psycho-echo-BFB is safe and inexpensive and allows all patients with anismus to relax PRM on straining. Previous anorectal surgery may be a negative predictor.

Large-conductance Ca(2+)-activated K(+) channels (BK, KCa1.1, MaxiK) are important regulators of urinary bladder function and may be an attractive therapeutic target in bladder disorders. In this study, we established a high-throughput fluorometric imaging plate reader-based screening assay for BK channel activators and identified a small-molecule positive modulator, NS19504 (5-[(4-bromophenyl)methyl]-1,3-thiazol-2-amine), which activated the BK channel with an EC50 value of 11.0 ± 1.4 µM. Hit validation was performed using high-throughput electrophysiology (QPatch), and further characterization was achieved in manual whole-cell and inside-out patch-clamp studies in human embryonic kidney 293 cells expressing hBK channels: NS19504 caused distinct activation from a concentration of 0.3 and 10 µM NS19504 left-shifted the voltage activation curve by 60 mV. Furthermore, whole-cell recording showed that NS19504 activated BK channels in native smooth muscle cells from guinea pig urinary bladder. In guinea pig urinary bladder strips, NS19504 (1 µM) reduced spontaneous phasic contractions, an effect that was significantly inhibited by the specific BK channel blocker iberiotoxin. In contrast, NS19504 (1 µM) only modestly inhibited nerve-evoked contractions and had no effect on contractions induced by a high K(+) concentration consistent with a K(+) channel-mediated action. Collectively, these results show that NS19504 is a positive modulator of BK channels and provide support for the role of BK channels in urinary bladder function. The pharmacologic profile of NS19504 indicates that this compound may have the potential to reduce nonvoiding contractions associated with spontaneous bladder overactivity while having a minimal effect on normal voiding., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Arachidonic acid (AA) is a polyunsaturated fatty acid involved in a complex network of cell signaling. It is well known that this fatty acid can directly modulate several cellular target structures, among them, ion channels. We explored the effects of AA on high conductance Ca(2+)- and voltage-dependent K(+) channel (BKCa) in vascular smooth muscle cells (VSMCs) where the presence of β1-subunit was functionally demonstrated by lithocholic acid activation. Using patch-clamp technique, we show at the single channel level that 10 μM AA increases the open probability (Po) of BKCa channels tenfold, mainly by a reduction of closed dwell times. AA also induces a left-shift in Po versus voltage curves without modifying their steepness. Furthermore, AA accelerates the kinetics of the voltage channel activation by a fourfold reduction in latencies to first channel opening. When AA was tested on BKCa channel expressed in HEK cells with or without the β1-subunit, activation only occurs in presence of the modulatory subunit. These results contribute to highlight the molecular mechanism of AA-dependent BKCa activation. We conclude that AA itself selectively activates the β1-associated BKCa channel, destabilizing its closed state probably by interacting with the β1-subunit, without modifying the channel voltage sensitivity. Since BKCa channels physiologically contribute to regulation of VSMCs contractility and blood pressure, we used the whole-cell configuration to show that AA is able to activate these channels, inducing significant cell hyperpolarization that can lead to VSMCs relaxation.

In this study, a fast algorithm was developed to capture of train of four and to filter extra contraction and noises. A low pass filter created to filter extra contraction and high frequency noises. Then, a TCA algorithm designed to capturing of the single twitch of muscle. The algorithm updated to remove embedded extra contraction and to derive boundary values in this location from cubic spline interpolation. Efficiency of TCA and effect of extra contraction tested in time and frequency domain.

Cardiac titin is the main determinant of sarcomere stiffness during diastolic relaxation. To explore whether titin stiffness affects the kinetics of cardiac myofibrillar contraction and relaxation, we used subcellular myofibrils from the left ventricles of homozygous and heterozygous N2B-knockout mice which express truncated cardiac titins lacking the unique elastic N2B region. Compared with myofibrils from wild-type mice, myofibrils from knockout and heterozygous mice exhibit increased passive myofibrillar stiffness. To determine the kinetics of Ca(2+)-induced force development (rate constant kACT), myofibrils from knockout, heterozygous and wild-type mice were stretched to the same sarcomere length (2.3 µm) and rapidly activated with Ca(2+). Additionally, mechanically induced force-redevelopment kinetics (rate constant kTR) were determined by slackening and re-stretching myofibrils during Ca(2+)-mediated activation. Myofibrils from knockout mice exhibited significantly higher kACT, kTR and maximum Ca(2+)-activated tension than myofibrils from wild-type mice. By contrast, the kinetic parameters of biphasic force relaxation induced by rapidly reducing [Ca(2+)] were not significantly different among the three genotypes. These results indicate that increased titin stiffness promotes myocardial contraction by accelerating the formation of force-generating cross-bridges without decelerating relaxation., (© 2014. Published by The Company of Biologists Ltd.)

The filament lattice in relaxed striated muscle is thought to be stabilized by electrostatic forces between charged filaments; electrostatic theories based on known filament charge densities do predict that the lattice spacing drops slightly with sarcomere length when actin and myosin filaments overlap. However, at sarcomere lengths with no overlap, electrostatic forces are reduced to a very low level and electrostatic models predict that the lattice collapses to a much smaller spacing. This collapse is not observed, which suggests that the A-band and I-band lattices are stabilized mechanically by the M-band and Z-line. To determine which mechanisms operate, consider a model where charged-filament interactions are supplemented by elastic titin filaments and radially elastic M-bands and Z-lines. To make progress, this model is simplified by assuming that the areas of A-band and Z-line unit cells are equal. Published data for the length-dependence of the lattice spacing, in and out of overlap, can be fitted to a mechanical model with known titin elasticity and very weak M-band or Z-line stiffness (≈0.15 pN/nm per unit cell), which implies that electrostatic interactions cannot be ignored. A better fit is obtained when electrostatic interactions are restored. Electrostatic interactions also explain why the lattice spacing of relaxed muscle is a decreasing function of temperature., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The aim of this study was to determine the mechanism of initiation of transient upper esophageal sphincter relaxation (TUESR) caused by gastric air distension. Cats (n = 31) were decerebrated, EMG electrodes were placed on the cricopharyngeus, a gastric fistula was formed, and a strain gauge was sewn on the lower esophageal sphincter (n = 8). Injection of air (114 ± 13 ml) in the stomach caused TUESR (n = 18) and transient lower esophageal sphincter relaxation (TLESR, n = 6), and this effect was not significantly (P > 0.05) affected by thoracotomy. Free air or bagged air (n = 6) activated TLESR, but only free air activated TUESR. Closure of the gastroesophageal junction blocked TUESR (9/9), but not TLESR (4/4), caused by air inflation of the stomach. Venting air from distal esophagus during air inflation of the stomach prevented TUESR (n = 12) but did not prevent air escape from the stomach to the esophagus (n = 4). Rapid injection of air on the esophageal mucosa always caused TUESR (9/9) but did not always (7/9) cause an increase in esophageal pressure. The time delay between the TUESR and the rapid air pulse was significantly more variable (P < 0.05) than the time delay between the rapid air pulse and the rise in esophageal pressure. We concluded that the TUESR caused by gastric air distension is dependent on air escape from the stomach, which stimulates receptors in the esophagus, but is not dependent on distension of the stomach or esophagus, or the TLESR. Therefore, the TUESR caused by gastric air distension is initiated by stimulation of receptors in the esophageal mucosa., (Copyright © 2014 the American Physiological Society.)

Background: It is unclear whether response time is affected by a stimulus cue, such as a light turned on or off, or if there are differences in response to these cues during a muscle contraction task compared with a muscle relaxation task. The objective of this study was to assess the response time of a relaxation task, including the contraction portion of the task, to a stimulus of a light turned on or off. In addition, we investigated the effect of the pre-contraction level on the relaxation task., Results: Contraction response time was significantly shorter during the light-on status than during the light-off status (P <0.01), and relaxation response time in each maximum voluntary contraction was significantly longer during the light-on status than during the light-off status (P <0.01). The relaxation response time became longer in order of 25% to 75% maximum voluntary contraction regardless of light-on or -off status, and was significantly longer than the contraction response time (P <0.05-0.01)., Conclusions: This study found that as the contraction level increased, the relaxation response time became longer than the contraction response time regardless of light status. However, contraction response time or relaxation response time findings were opposite to this during the light-on status and light-off status: contraction response time became shorter in the light-on status than in the light-off status and relaxation response time became longer in the light-on status than in the light-off status. These results suggest that the length of each response time is affected by motor control in the higher order brain and involves specific processing in the visual system.

Objective: Individuals with chronic whiplash-associated disorders (WADs) often note driving as a difficult task. This study's aims were to (1) compare, while driving, neck motor performance, mental effort, and fatigue in individuals with chronic WAD against healthy controls and (2) investigate the relationships of these variables and neck pain to self-reported driving difficulty in the WAD group., Design: This study involved 14 participants in each group (WAD and control). Measures included self-reported driving difficulty and measures of neck pain intensity, overall fatigue, mental effort, and neck motor performance (head rotation and upper trapezius activity) while driving a simulator., Results: The WAD group had greater absolute path of head rotation in a simulated city area and used greater mental effort (P = 0.04), but there were no differences in other measures while driving compared with the controls (all P ≥ 0.05). Self-reported driving difficulty correlated moderately with neck pain intensity, fatigue level, and maximum velocity of head rotation while driving in the WAD group (all P < 0.05)., Conclusions: Individuals with chronic WAD do not seem to have impaired neck motor performance while driving yet use greater mental effort. Neck pain, fatigue, and maximum head rotation velocity could be potential contributors to self-reported driving difficulty in this group.

Introduction: The timed "up & go" (TUG) test is a quick measure of balance and mobility. TUG scores correlate with clinical, functional, and strength assessment and decline linearly over time. Reliability and validity have not been tested in spinal muscular atrophy (SMA)., Methods: Fifteen ambulatory SMA participants performed TUG testing and strength, functional, and clinical assessments. Intraclass correlation coefficients quantified test-retest reliability. Convergent validity was determined using Pearson correlation coefficients., Results: Test-retest reliability was excellent for all participants. TUG was associated significantly with total leg and knee flexor strength, as well as the Hammersmith Functional Motor Scale Expanded, the 10-meter walk/run, and 6-minute walk tests. TUG findings were not associated with knee extensor strength, pulmonary function, or fatigue., Conclusions: In SMA, the TUG test is easily administered, reliable, and correlates with established outcome measures. TUG testing is a potentially useful outcome measure for clinical trials and a measure of disability in ambulatory patients with SMA., (Copyright © 2013 Wiley Periodicals, Inc.)

Introduction: A conditioning maximal voluntary muscle action (MVC) has been shown to induce postactivation potentiation, that is, improved contractile muscle properties, when muscles are contracted isometrically. It is still uncertain how the contractile properties are affected during ongoing muscle length changes. The purpose of this study was to investigate the effects of a 6-s conditioning MVC on twitch properties of the plantarflexors during ongoing muscle length changes., Methods: Peak twitch, rate of torque development, and rate of torque relaxation, rising time, and half relaxation time were measured from supramaximal twitches evoked in the plantarflexors of 11 highly trained athletes. Twitches were evoked before a 6-s MVC and subsequently on eight different occasions during a 10-min recovery for five different modes: fast lengthening, slow lengthening, isometric, fast shortening, and slow shortening of the plantarflexors., Results: The magnitude and the duration of effects from the conditioning MVC were significantly different between modes. Peak twitch, rate of torque development, and rate of torque relaxation significantly increased for all modes but more so for twitches evoked during fast and slow shortening as compared with lengthening. Rising time was reduced in the lengthening modes but slightly prolonged in the shortening modes. Half relaxation time was significantly reduced for all modes, except fast lengthening., Conclusions: The findings show that the effects of a conditioning MVC on twitch contractile properties are dependent on direction and velocity of ongoing muscle length changes. This may imply that functional enhancements from a conditioning MVC might be expected to be greatest for concentric muscle actions but are still present in isometric and eccentric parts of a movement.

The purpose of this study was to describe the performance and biomechanical parameters of the counter-movement jump for young people with ID, in comparison with age matched individuals without ID. Volunteers with ID (n=13; age=15.3 ± 1.6 years; Wisk III intelligence quotient 55.6 ± 11.2) and without ID (n=13; age=15.4 ± 1.2 years) performed maximal counter-movement jumps, while knee kinematics, vertical ground reaction forces and electromyographic activity of the vastus lateralis and biceps femoris were captured. Individuals without ID jumped higher than their counterparts with ID and had lower take-off velocity, lower knee joint power and stiffness, lower knee joint extension angle and angular velocity, longer braking and propulsion phase, lower agonist and higher antagonist EMG activity. These results give an insight on possible causes for the performance deficit in CMJ in persons with ID and give the potential for such individuals to improve their ability to jump higher and more efficiently., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: This study compared immediate versus delayed massage-like compressive loading on skeletal muscle viscoelastic properties following eccentric exercise., Methods: Eighteen rabbits were surgically instrumented with peroneal nerve cuffs for stimulation of the tibialis anterior muscle. Rabbits were randomly assigned to a massage loading protocol applied immediately post exercise (n=6), commencing 48h post exercise (n=6), or exercised no-massage control (n=6). Viscoelastic properties were evaluated in vivo by performing a stress-relaxation test pre- and post-exercise and daily pre- and post-massage for four consecutive days of massage loading. A quasi-linear viscoelastic approach modeled the instantaneous elastic response (AG0), fast (g1(p)) and slow (g2(p)) relaxation coefficients, and the corresponding relaxation time constants τ1 and τ2., Findings: Exercise increased AG0 in all groups (P<0.05). After adjusting for the three multiple comparisons, recovery of AG0 was not significant in the immediate (P=0.021) or delayed (P=0.048) group compared to the control group following four days of massage. However, within-day (pre- to post-massage) analysis revealed a decrease in AG0 in both massage groups. Following exercise, g1(p) increased and g2(p) and τ1 decreased for all groups (P<0.05). Exercise had no effect on τ2 (P>0.05). After four days of massage, there was no significant recovery of the relaxation parameters for either massage loading group compared to the control group., Interpretation: Our findings suggest that massage loading following eccentric exercise has a greater effect on reducing muscle stiffness, estimated by AG0, within-day rather than affecting recovery over multiple days. Massage loading also has little effect on the relaxation response., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aims: The current study investigates the role played by bradykinin (BK) receptors in the contractility to the pig bladder neck smooth muscle., Methods: Bladder neck strips were mounted in myographs for isometric force recordings and BK receptors expression was also determined by immunohistochemistry., Results: B2 receptor expression was observed in the muscular layer and urothelium whereas B1 expression was consistent detected in urothelium. A strong B2 immunoreactivity was also observed within nerve fibers among smooth muscle bundles. On urothelium-denuded preparations basal tone, BK induced concentration-dependent contractions which were reduced in urothelium-intact samples, by extracellular Ca(2+) removal and by blockade of B2 receptors and voltage-gated Ca(2+) (VOC) and non-VOC channels, and increased by cyclooxygenase (COX) inhibition. On phenylephrine-precontracted denuded strips, under non-adrenergic non-cholinergic (NANC) conditions, electrical field stimulation-elicited frequency-dependent relaxations which were reduced by B2 receptor blockade. In urothelium-intact samples, the B1 receptor agonist kallidin promoted concentration-dependent relaxations which were reduced by blockade of B1 receptors, COX, COX-1 and large-conductance Ca(2+) -activated K(+) (BKCa ) channels and abolished in urothelium-denuded samples and in K(+) -enriched physiological saline solution-precontracted strips., Conclusions: These results suggest that BK produces contraction of pig bladder neck via smooth muscle B2 receptors coupled to extracellular Ca(2+) entry via VOC and non-VOC channels with a minor role for intracellular Ca(2+) mobilization. Facilitatory neuronal B2 receptors modulating NANC inhibitory neurotransmission and urothelial B1 receptors producing relaxation via the COX-1 pathway and BKCa channel opening are also demonstrated. Neurourol. Urodynam. 33:558-565, 2014. © 2013 Wiley Periodicals, Inc., (© 2013 Wiley Periodicals, Inc.)

Patients with low back pain often demonstrate elevated paraspinal muscle activity compared to asymptomatic controls. This hyperactivity has been associated with a delayed rate of stature recovery following spinal loading tasks. The aim of this study was to investigate the changes in muscle activity and stature recovery in patients with chronic low back pain following an active rehabilitation programme. The body height recovery over a 40-min unloading period was assessed via stadiometry and surface electromyograms were recorded from the paraspinal muscles during standing. The measurements were repeated after patients had attended the rehabilitation programme and again at a six-month follow-up. Analysis was based on 17 patients who completed the post-treatment analysis and 12 of these who also participated in the follow-up. By the end of the six months, patients recovered significantly more height during the unloading session than at their initial visit (ES = 1.18; P < 0.01). Greater stature recovery immediately following the programme was associated with decreased pain (r = -0.55; P = 0.01). The increased height gain after six months suggests that delayed rates of recovery are not primarily caused by disc degeneration. Muscle activity did not decrease after treatment, perhaps reflecting a period of adaptation or altered patterns of motor control., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The receptors responsible for taste perception distinguish the four basic tastes : salty, sweet, bitter and umami. Among them, the bitter taste receptors (TAS2R) are G protein coupled receptors, including 25 subtypes identified in humans to date. Although the existence of endogenous agonists remains uncertain, the TAS2R receptors have the ability to recognize natural or synthetic molecules, as various molecules produced by bacteria, or caffeine, chloroquine, or erythromycin. The expression of these receptors, initially thought to be confined to the oral cavity, has recently been described in extra-oral tissues such as the gastrointestinal tract and the lungs. The effects in the lung tissue are essentially at three levels : TAS2R receptors expressed on the cilia of epithelial cells increase the cilia vibration frequency; the stimulation of TAS2R receptors expressed in bronchial smooth muscle cells leads to bronchial relaxation; while TAS2R receptors expressed on immune cells in the lung tissue, including macrophages, are involved in the modulation of the production of pro-inflammatory cytokines. In conclusion, in view of these complementary mechanisms, TAS2R receptors may become a pharmacological target of interest for the treatment of obstructive lung diseases., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Introduction: Endothelin 1 (ET-1) levels and receptors are up-regulated in the erectile tissue of diabetic patients and animal models of erectile dysfunction (ED)., Aim: The present study assessed the role of ET-1 receptors in the impaired adrenergic vasoconstriction and nitrergic relaxation of penile arteries from a rat model of insulin resistance., Methods: The effect of ET receptor antagonists was evaluated on the contractile responses to electrical field stimulation (EFS) of penile arteries from obese Zucker rats (OZRs) compared with lean Zucker rats (LZRs). ET receptor expression was determined by immunohistochemistry., Main Outcome Measures: Changes in neural nitrergic relaxation and adrenergic vasoconstriction and the expression of ET receptors in perivascular nerves were assessed., Results: ET-1 (10(-10)  M) enhanced EFS-induced vasoconstriction, and treatment with the adrenergic neurotoxin guanethidine reduced the contractions induced by ET-1 in penile arteries from both LZRs and OZRs, thus supporting the hypothesis that ET-1 releases noradrenaline from adrenergic nerves. ET-1 antagonized neural nitric oxide (NO)-mediated relaxant responses in LZR arteries, antagonizing relaxations induced by the NO donor S-nitroso-N-acetylpenicillamine to a larger extent in arteries from OZRs. ET(A) and ET(B) receptors were expressed in perivascular fibers colocalized with the neuronal marker protein gene product 9.5 in penile arteries from OZRs. The ET(A) receptor antagonist BQ-123 reversed the enhancing effect of ET-1 on the vasoconstriction elicited by EFS and the ET-1-induced inhibition of nitrergic relaxations in LZRs, restoring them to control levels in penile arteries of OZRs., Conclusions: ET-1 enhances adrenergic vasoconstriction through presynaptic ET(A) receptors and antagonizes neural NO-mediated relaxation through postsynaptic smooth muscle ET(A) receptors in penile arteries from OZRs, which likely contributes to the augmented vasoconstriction and blunted nitrergic relaxation of erectile tissue under conditions of insulin resistance., (© 2014 International Society for Sexual Medicine.)

Aims: The study proposes Acoustic Radiation Force Impulse (ARFI) assessment of the masseter muscle elasticity in the healthy population and in patients who have undergone head and neck radiation therapy., Patients and Methods: Twenty-five healthy controls constituted group A, and 13 patients who had underwent radiotherapy (35Gy minimum) formed group B. ARFI was performed bilaterally in the periphery (P) and the muscle center (C), in relaxation and contraction. Means and standard deviations were obtained for the recorded shear waves velocities (SWV)., Results: For group A: in the relaxed right muscle C = 1.87±0.52 m/s and P = 1.96 ±0.55 m/s and in the left muscle C = 1.66 +/- 0.47 m/s, P = 1.67 +/-0.53 m/s. For group B, in relaxation, the right side presented C = 1.67 +/-0.6 m/s, P 1.72 +/-0.56 m/s, the left muscle C = 1.6 +/-0.34 m/s, P = 1.73 +/-0.37 m/s. There were no differences (p> 0.05) between P and C of both groups, regardless of the muscle state. The values for relaxation and contraction in A and B (merged values of the right and left) presented no differences (1.79+/-0.52 m/s vs 1.72 +/-0.73 m/s, p = 0.72 and 1.70 +/-0.48 m/s and vs 1.59 +/-0.77 m/s, p = 0.98). All measurements of group A vs B were not different (1.79 +/-0.52 m/s vs 1.65 +/-0.63 m/s, p = 0.78)., Conclusions: ARFI with SWV measurement enables the quantification of normal and post irradiation elasticity of the masseter. Further studies on a larger population are required to validate the normal and pathologic values.

Myogenic regulatory factors such as MyoD and Myf5 lie at the core of vertebrate muscle differentiation. However, E-boxes, the cognate binding sites for these transcription factors, are not restricted to the promoters/enhancers of muscle cell-specific genes. Thus, the specificity in myogenic transcription is poorly defined. Here we describe the transcription factor Ebf3 as a new determinant of muscle cell-specific transcription. In the absence of Ebf3 the lung does not unfold at birth, resulting in respiratory failure and perinatal death. This is due to a hypercontractile diaphragm with impaired Ca(2+) efflux-related muscle functions. Expression of the Ca(2+) pump Serca1 (Atp2a1) is downregulated in the absence of Ebf3, and its transgenic expression rescues this phenotype. Ebf3 binds directly to the promoter of Atp2a1 and synergises with MyoD in the induction of Atp2a1. In skeletal muscle, the homologous family member Ebf1 is strongly expressed and together with MyoD induces Atp2a1. Thus, Ebf3 is a new regulator of terminal muscle differentiation in the diaphragm, and Ebf factors cooperate with MyoD in the induction of muscle-specific genes.

This study investigated the involvement of sensory nerves and, in particular, neuronal transient receptor potential vanilloid (TRPV) 1 channels, in the CO(2)-mediated regulation of cerebrovascular tone. Basilar artery diameter and blood flow velocity in the ventral midbrain were determined in a rat cranial window preparation by digital imaging and laser-Doppler flowmetry, respectively. Superfusion of the basilar artery with capsaicin, a selective TRPV1 receptor agonist, caused a transient relaxation, consistent with acute desensitization of neuronal TRPV1 channels. Constriction to respiratory hypocapnia remained unaffected following capsaicin superfusion. Denervation of sensory nerves by repeated capsaicin injection of neonates also did not reduce the respiratory hypocapnia constriction of the basilar artery as well as the decreased flow velocity in the ventral midbrain in adults. These findings suggest that sensory nerves and, in particular, neuronal TRPV1 channels, do not play a role in respiratory hypocapnia constriction and decreased flow, at least in rat basilar artery and ventral midbrain., (Published by Elsevier B.V.)

Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively. Measurements were made at baseline and after NTG given systemically (800 μg sublingually, n=20) and locally by intracoronary infusion (1 μg/min; n=10). Systemic NTG had no significant effect on first shoulder pressure but reduced augmentation (and central pulse pressure) by 12.8±3.1 mm Hg (P<0.0001). This resulted from a reduction in forward and backward wave components of AP by 7.0±2.4 and 5.8±1.3 mm Hg, respectively (each P<0.02). NTG had no significant effect on the ratio of amplitudes of either backward/forward waves or backward/forward compression wave energies, suggesting that effects on the backward wave were largely secondary to those on the forward wave. Time to the forward expansion wave was reduced (P<0.05). Intracoronary NTG decreased AP by 8.3±3.6 mm Hg (P<0.05) with no significant effect on the backward wave. NTG reduces AP and central pulse pressure by a mechanism that is, at least in part, independent of arterial reflections and relates to ventricular contraction/relaxation dynamics with enhanced myocardial relaxation.

Aim: By a combined electromyographic (EMG), mechanomyographic (MMG) and force (F) analysis, the electromechanical delay during muscle relaxation (R-DelayTOT ) was partitioned into electrochemical and mechanical components. The study aimed to evaluate the effects of fatigue on R-DelayTOT components and to assess their intersession and interday reliability Intraclass correlation coefficient (ICC)., Methods: During tetanic stimulations, EMG, MMG and F were recorded from the human gastrocnemius medialis muscle before and after fatigue. The latency between EMG and MMG ripple cessations (R-Δt EMG-MMGR , electrochemical R-DelayTOT component); between MMG ripple cessation and F decay onset (R-Δt MMGR -F, first R-DelayTOT mechanical component); and between F decay onset and maximum MMG negative peak (R-Δt F-MMGp-p , second R-DelayTOT mechanical component) was calculated., Results: Before fatigue, R-Δt F-MMGp-p was the major contributor (61.9 ± 1.7 ms, 75%) to R-DelayTOT (82.7 ± 1.0 ms), while R-Δt EMG-MMGR and R-Δt MMGR -F accounted for 16% (13.3 ± 1.2 ms) and 9% (7.5 ± 1.0 ms) respectively. After fatigue, R-DelayTOT , R-Δt EMG-MMGR and R-Δt MMGR -F increased by 11, 41 and 67%, respectively (P < 0.05), whereas R-Δt F-MMGp-p did not change. Consequently, the relative contribution of R-Δt EMG-MMGR , R-Δt MMGR -F and R-Δt F-MMGp-p , to R-DelayTOT changed to 20 ± 2, 12 ± 1 and 68 ± 2% respectively. Measurement reliability was always from high to very high (ICC 0.705-0.959)., Conclusion: Fatigue altered the processes between neuromuscular activation cessation and force decay onset, but not the second mechanical component (cross-bridges detachment rate and series elastic components release). This combined approach provided reliable measurement of the different R-DelayTOT components and it may represent a valid tool to get more insights on muscle electromechanical behaviour., (© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Estrogens have been recognized, in the last 3 decades, as important hormones in direct and indirect modulation of vascular health. In addition to their direct benefit on cardiovascular health, the presence of esterified estrogen in the lipid core of high-density lipoprotein (HDL) particles indirectly contributes to atheroprotection by significantly improving HDL quality and functionality. Estrogens modulate their physiological activity via genomic and nongenomic mechanisms. Genomic mechanisms are thought to be mediated directly by interaction of the hormone receptor complex with the hormone response elements that regulate gene expression. Nongenomic mechanisms are thought to occur via interaction of the estrogen with membrane-bound receptors, which rapidly activate intracellular signaling without binding of the hormone receptor complex to its hormone response elements. Estradiol in particular mediates early and late endothelial nitric oxide synthase (eNOS) activation via interaction with estrogen receptors through both nongenomic and genomic mechanisms. In the vascular system, the primary endogenous source of nitric oxide (NO) generation is eNOS. Nitric oxide primarily influences blood vessel relaxation, the heart rate, and myocyte contractility. The abnormalities in expression and/or functions of eNOS lead to the development of cardiovascular diseases, both in animals and in humans. Although considerable research efforts have been dedicated to understanding the mechanisms of action of estradiol in regulating cardiac eNOS, more research is needed to fully understand the details of such mechanisms. This review focuses on recent findings from animal and human studies on the regulation of eNOS and HDL quality by estradiol in cardiovascular pathology.

Objectives: Reflex anal dilatation (RAD) is considered as a possible sign of anal abuse,however studies evaluating its prevalence in non-abused children are limited. The aim of this study was to evaluate the prevalence of RAD in a convenience sample of children with no suspicion of abuse admitted to a Pediatric Emergency Department (PED)., Methods: Prospective observational study including children admitted to the PED of Padova, Italy, between January and June 2011. Patients with no suspicion of abuse and for whom ano-genital examination was part of their medical evaluation were included. Children were excluded if in critical clinical conditions or if any suspicion of abuse arose during medical evaluation. Presence/absence of RAD and of factors favoring its appearance were recorded for each patient., Results: Two-hundred and thirty children (median age of 12 months, interquartile range 5-35 months) were finally included. A positive RAD was reported in 14 (6.1%, CI 95% 3.4-10). Only 3 patients (1.3%, CI 95% 0.3-3.7) showed a positive RAD in the absence of any predisposing factor., Conclusions: RAD is an infrequent sign in non-abused children and it is particularly rare in the absence of any predisposing factor. Case-control studies are necessary to better clarify its diagnostic relevance., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To explore motor excitability changes induced by disobedience and feigning-like behaviour., Methods: Healthy subjects participated in motor imagery tasks. They imagined either a maximum muscle relaxation (condition 1) or a pinch grip (condition 2). In other trials, they were instructed to disobey the command to imagine a pinch grip. Instead, they should either imagine a maximum muscle relaxation (condition 3) or think of something else which they could choose freely (condition 4). Transcranial magnetic stimulation was used to explore motor excitability during the different tasks. Motor evoked potential amplitudes were expressed as percentage of the task-free control condition (condition 5)., Results: Imagination of a pinch grip enhanced motor excitability, imagery of maximum muscle relaxation reduced motor excitability below the level of the control condition. In conditions 3 and 4, motor excitability was lower than in condition 2. However, motor excitability in condition 3 was higher than in condition 1., Conclusions: Healthy subjects successfully disobeyed the motor imagery command but failed to maintain the down-regulation of motor excitability when trying to imagine maximum muscle relaxation., Significance: The results help to interpret the down-regulation of motor excitability found in patients with motor conversion disorder., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Elevation of intracellular cAMP and activation of protein kinase A (PKA) lead to activation of large conductance voltage- and Ca(2+)-activated K(+) (BK) channels, thus attenuation of detrusor smooth muscle (DSM) contractility. In this study, we investigated the mechanism by which pharmacological inhibition of cAMP-specific phosphodiesterase 4 (PDE4) with rolipram or Ro-20-1724 (C(15)H(22)N(2)O(3)) suppresses guinea pig DSM excitability and contractility. We used high-speed line-scanning confocal microscopy, ratiometric fluorescence Ca(2+) imaging, and perforated whole-cell patch-clamp techniques on freshly isolated DSM cells, along with isometric tension recordings of DSM isolated strips. Rolipram caused an increase in the frequency of Ca(2+) sparks and the spontaneous transient BK currents (TBKCs), hyperpolarized the cell membrane potential (MP), and decreased the intracellular Ca(2+) levels. Blocking BK channels with paxilline reversed the hyperpolarizing effect of rolipram and depolarized the MP back to the control levels. In the presence of H-89 [N-[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide dihydrochloride], a PKA inhibitor, rolipram did not cause MP hyperpolarization. Rolipram or Ro-20-1724 reduced DSM spontaneous and carbachol-induced phasic contraction amplitude, muscle force, duration, and frequency, and electrical field stimulation-induced contraction amplitude, muscle force, and tone. Paxilline recovered DSM contractility, which was suppressed by pretreatment with PDE4 inhibitors. Rolipram had reduced inhibitory effects on DSM contractility in DSM strips pretreated with paxilline. This study revealed a novel cellular mechanism whereby pharmacological inhibition of PDE4 leads to suppression of guinea pig DSM contractility by increasing the frequency of Ca(2+) sparks and the functionally coupled TBKCs, consequently hyperpolarizing DSM cell MP. Collectively, this decreases the global intracellular Ca(2+) levels and DSM contractility in a BK channel-dependent manner.

Here we explored the impact of hydrogen sulfide (H2S) on biophysical properties of the primary human airway smooth muscle (ASM)-the end effector of acute airway narrowing in asthma. Using magnetic twisting cytometry (MTC), we measured dynamic changes in the stiffness of isolated ASM, at the single-cell level, in response to varying doses of GYY4137 (1-10mM). GYY4137 slowly released appreciable levels of H2S in the range of 10-275 μM, and H2S released was long lived. In isolated human ASM cells, GYY4137 acutely decreased stiffness (i.e. an indicator of the single-cell relaxation) in a dose-dependent fashion, and stiffness decreases were sustained in culture for 24h. Human ASM cells showed protein expressions of cystathionine-γ-lyase (CSE; a H2S synthesizing enzyme) and ATP-sensitive potassium (KATP) channels. The KATP channel opener pinacidil effectively relaxed isolated ASM cells. In addition, pinacidil-induced ASM relaxation was completely inhibited by the treatment of cells with the KATP channel blocker glibenclamide. Glibenclamide also markedly attenuated GYY4137-mediated relaxation of isolated human ASM cells. Taken together, our findings demonstrate that H2S causes the relaxation of human ASM and implicate as well the role for sarcolemmal KATP channels. Finally, given that ASM cells express intrinsic enzymatic machinery of generating H2S, we suggest thereby this class of gasotransmitter can be further exploited for potential therapy against obstructive lung disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purines induce transient contraction and prolonged relaxation of detrusor muscles. Transient contraction could be due to activation of inward currents in smooth muscle cells, but the mechanism of purinergic relaxation has not been determined. We recently reported a new class of interstitial cells in detrusor muscles and showed that these cells could be identified with antibodies against platelet-derived growth factor receptor-α (PDGFRα(+) cells). The current density of small conductance Ca(2+)-activated K(+) (SK) channels in these cells is far higher (∼100 times) than in smooth muscle cells. Thus, we examined purinergic receptor (P2Y) mediated SK channel activation as a mechanism for purinergic relaxation. P2Y receptors (mainly P2ry1 gene) were highly expressed in PDGFRα(+) cells. Under voltage clamp conditions, ATP activated large outward currents in PDGFRα(+) cells that were inhibited by blockers of SK channels. ATP also induced significant hyperpolarization under current clamp conditions. A P2Y1 agonist, MRS2365, mimicked the effects of ATP, and a P2Y1 antagonist, MRS2500, inhibited ATP-activated SK currents. Responses to ATP were largely abolished in PDGFRα(+) cells of P2ry1(-/-) mice, and no response was elicited by MRS2365 in these cells. A P2X receptor agonist had no effect on PDGFRα(+) cells but, like ATP, activated transient inward currents in smooth muscle cells (SMCs). A P2Y1 antagonist decreased nerve-evoked relaxation. These data suggest that purines activate SK currents via mainly P2Y1 receptors in PDGFRα(+) cells. Our findings provide an explanation for purinergic relaxation in detrusor muscles and show that there are no discrete inhibitory nerve fibres. A dual receptive field for purines provides the basis for inhibitory neural regulation of excitability.

Background: Characterizing the lumbar muscle flexion-relaxation phenomenon is a clinically relevant approach in understanding the neuromuscular alternations of low back pain patients. Previous studies have indicated that changes in stance posture could directly influence trunk kinematics and potentially change the lumbar tissue synergy. In this study, the effects of stance width and foot posture on the lumbar muscle relaxation responses during trunk flexion were investigated., Methods: Thirteen volunteers performed trunk flexion using three different stance widths and 'toe-forward' or 'toe-out' foot postures (six conditions in total). Lumbar muscle electromyography was collected from the L3 and L4 level paraspinals; meanwhile three magnetic motion sensors were placed over the S1, T12, and C7 vertebrae to track lumbar and trunk kinematics. The lumbar angle at which muscle activity diminished to a near resting level was recorded. At the systemic level, the boundary where the internal moment started to shift from active to passive tissues was identified., Findings: For the L3 paraspinals, the flexion relaxation lumbar angle reduced 1.3° with the increase of stance width. When changed from 'toe-forward' to 'toe-out' foot posture, the flexion relaxation lumbar angle reduced 1.4° and 1.1° for the L3 and L4 paraspinals respectively. However, the active and passive lumbar tissue load shifting boundary was not affected., Interpretation: Findings of this study suggest that changes in stance width and foot posture altered the lumbar tissue load sharing mechanism. Therefore, in a clinical setting, it is critical to maintain consistent stance postures when examining the characteristics of lumbar tissue synergy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Neck pain is common among general population with a high prevalence among the people who are routinely exposed to prolonged use of static head-neck postures. Prolonged static loading can cause localized muscle fatigue which may impact the stability of the cervical spine. In this study, flexion-relaxation phenomenon was used to study the post fatigue changes in the stability of cervical spine by evaluating the synergistic load sharing between muscles and viscoelastic elements., Methods: Thirteen male participants were recruited for data collection. The variables that influence cervical flexion-relaxation were studied pre- and post-fatigue using neutral and shrugged shoulder postures. The Sorensen protocol was used to induce neck extensor fatigue. Surface electromyography and optical motion capture systems were used to record neck muscle activation and head posture, respectively. Findings The flexion-relaxation phenomenon was observed only in the neutral shoulder position pre- and post-fatigue. The flexion relaxation ratio decreased significantly post-fatigue in neutral shoulder position but remained unchanged in shrugged shoulder position. The onset and offset angles and the corresponding durations of the silence period were significantly affected by the fatigue causing a post-fatigue expansion of silence period. Interpretation The muscular fatigue of neck extensors and shoulder position was found to modulate the cervical flexion-relaxation phenomenon. Early shifting of load sharing under fatigued condition indicates increased demands on the passive tissues to stabilize the cervical spine. Shrugging of shoulder seems to alter muscular demands of neck extensors and make cervical flexion-relaxation phenomenon disappear due to continuous activation of the neck extensors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives/hypothesis: To study the laryngeal electromyography pattern in patients with Parkinson's disease (PD) and vocal complaints at different stages of the disease., Study Design: Cross-sectional cohort study., Methods: Ninety-four adults with PD and vocal complaints at different stages of the disease (according to the Hoehn and Yahr scale) underwent laryngeal electromyography., Results: Tremors were not detected on laryngeal electromyography of the cricothyroid and thyroarytenoid muscles even in patients with clinical tremor. Laryngeal electromyography hypercontractility during voice rest was the typical result observed in 91.5% of patients regardless of disease severity. Gender and age of subjects did not correlate with laryngeal electromyography results. Patients with PD presented spontaneous intrinsic laryngeal muscle activity during voice rest, regardless of disease severity., Conclusions: This study was significant because it reported on the use of laryngeal electromyography in a large number of patients with PD and vocal complaints grouped according to PD severity. The patterns observed suggest that laryngeal electromyography is a valuable diagnostic tool for PD even at early phases of the disease., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)