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A randomized control trial was conducted to assess the effectiveness of progressive muscle relaxation and deep breathing exercises on pain, disability, and sleep quality among patients with chronic tension-type headache. Of the 169 randomly selected patients, 84 performed the intervention and reported less pain severity and disability and better sleep quality after 12 weeks., Competing Interests: No conflict of interest among authors to be declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Urinary bladder dysfunction might be related to disturbances at different levels of the micturition reflex arc. The current study aimed to further develop and evaluate a split bladder model for detecting and analysing relaxatory signalling in the rat urinary bladder. The model allows for discrimination between effects at the efferent and the afferent side of the innervation. In in vivo experiments, the stimulation at a low frequency (1 Hz) of the ipsilateral pelvic nerve tended to evoke relaxation of the split bladder half (contralateral side; -1.0 ± 0.4 mN; n = 5), in contrast to high frequency-evoked contractions. In preparations in which the contralateral pelvic nerve was cut the relaxation occurred at a wider range of frequencies (0.5-2 Hz). In separate experiments, responses to 1 and 2 Hz were studied before and after intravenous injections of propranolol (1 mg/kg IV). The presence of propranolol significantly shifted the relaxations into contractions. Also, electrical stimulation of the ipsilateral pudendal nerve evoked relaxations of similar magnitude as for the pelvic stimulations, which were also affected by propranolol. In control in vitro experiments, substances with β-adrenoceptor agonism, in contrast to a selective α-agonist, evoked relaxations. The current study shows that the split bladder model can be used for in vivo studies of relaxations. In the model, reflex-evoked sympathetic responses caused relaxations at low intensity stimulation. The involvement of β-adrenoceptors is supported by the sensitivity to propranolol and by the in vitro observations., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objective: This single-blind, randomized controlled study aimed to determine the effect of progressive muscle relaxation exercises on sleep quality and fatigue in the postmenopausal period. Progressive muscle relaxation aims to relax the muscles in the body and includes breathing techniques., Methods: This study was carried out between January 2022 and July 2022 with 63 postmenopausal women who applied to a district state hospital and had poor sleep quality. The women assigned to the experimental group (EG) (n = 31) applied progressive muscle relaxation exercises every day for 8 weeks. In contrast, the women in the control group (CG) (n = 32) continued their routine coping habits related to sleep problems and fatigue in the postmenopausal period. The EG and CG were reevaluated using the Piper Fatigue Scale and the Pittsburg Sleep Quality Index in the fourth and eighth weeks. The women applied progressive muscle relaxation exercises with a guide prepared by the researchers and the compact disc of the Turkish Psychologists Association. In the data analysis, the independent-samples t test, Fisher's exact test, and χ2 test were used to compare individual, obstetric, and medical characteristics between the groups. The difference between dependent groups at different times was evaluated by repeated-measures analysis of variance., Results: There was an improvement in fatigue symptoms in the progressive muscle relaxation exercises-performing EG at the end of 8 weeks compared with the CG, and fatigue symptoms increased in the CG (P < 0.001). There was a greater improvement in the sleep quality of the progressive muscle relaxation exercises-performing EG at the end of 8 weeks compared with the CG (P < 0.001)., Conclusions: In our study, it was determined that progressive muscle relaxation exercises had an improving effect on sleep quality and fatigue., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2024 by The Menopause Society.)

Background: Shoulder dislocation, particularly anterior dislocation, is a common orthopedic injury often presenting in emergency care settings, characterized by significant pain and muscle spasms. Prompt reduction is essential to alleviate symptoms and restore function. The Cunningham technique employs gentle pulling and massage motions targeted at the muscles and has emerged as a promising method for reducing anterior shoulder dislocations. However, its reported success rates vary widely across studies, and questions remain regarding its efficacy, particularly in cases of failure. This study aims to evaluate the effectiveness of the Cunningham technique for reducing anterior shoulder dislocations and its potential role in providing analgesia and muscle relaxation as an adjunctive method., Methods: A retrospective study was conducted on patients presenting with acute anterior shoulder dislocation at a single center. Reduction using the Cunningham technique was performed initially, followed by the external rotation technique if unsuccessful. Procedural sedation and analgesia were administered if the reduction was still not achieved, and shoulder dislocation reduction was performed again through the external rotation method. The patients' VAS scores were recorded and evaluated the Cunningham technique's effectiveness in reduction and whether it increases the effectiveness of other techniques applied for reduction by lowering the VAS score, even in cases where it is not effective., Results: A total of 61 patients were included in the study. The reduction was performed using the Cunningham technique in 34.4% (21/61) patients, the external rotation technique in 47.5% (29/61) patients, and the external rotation technique with PSA in 18% (11/61) patients. Significant differences were observed in the duration of hospital stay among the three techniques, with ER with PSA resulting in the longest stay. VAS scores showed significant improvements from initial presentation to post-reduction in all three groups. A significant decrease in pre-reduction VAS scores was observed during the transition from the Cunningham technique to other techniques., Conclusion: The Cunningham technique showed effectiveness in reducing anterior shoulder dislocations, providing analgesia, and muscle relaxation. It demonstrated favorable outcomes as an initial reduction technique, with the external rotation technique used as a subsequent option. Further studies comparing the success rates and complications of the Cunningham technique with other reduction methods are warranted to establish its role in clinical practice., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Abstract: The relaxation of trapezius muscles is widely believed to alleviate fatigue or injury of the trapezius muscles and reduce the risk of shoulder and neck pain. This study aims to examine the effects of different muscle relaxation techniques on the physical properties of the trapezius muscle and to explore how changes in the physical properties of the upper trapezius muscle affect those of the middle trapezius muscle. Twenty-four healthy males (mean age: 23.08 ± 0.97 years; height: 172.42 ± 4.61 cm; weight: 66.38 ± 6.68 kg; and body mass index: 22.30 ± 1.81 kg/m2), randomly divided into four groups: stretching relaxation group (ST, n = 6), mechanical vibration massage (MV, n = 6), pulse massage (PU, n = 6), and control (CO, n = 6). Measurements using the Myoton digital muscle assessment system were conducted daily over 2 weeks. The experimental groups demonstrated a notable decrease in tension and stiffness, accompanied by heightened elasticity in the upper trapezius muscles. Conversely, the control group exhibited contrasting trends. Although no significant variances were detected among the relaxation techniques, all proved efficacious compared to the control group (P < 0.05). Moreover, relaxation of the upper trapezius muscles significantly influenced the middle trapezius muscles (P < 0.05). Various relaxation methods positively influenced trapezius muscle attributes over 2 weeks, with inter-regional effects noted., (Copyright © 2024 Copyright: © 2024 Journal of Physiological Investigation.)

Background: This study investigated the relaxation effect of PGE2 on the ureter and its role in promoting calculi expulsion following calculi development., Methods: By using immunofluorescence and Western blot, we were able to locate EP receptors in the ureter. In vitro experiments assessed the impact of PGE2, receptor antagonists, and agonists on ureteral relaxation rate. We constructed a model of ureteral calculi with flowable resin and collected ureteral tissue from postoperative side of the ureter after obstruction surgery. Western blot analysis was used to determine the protein expression levels of EP receptors and the PGE2 terminal synthase mPGES-1. Additionally, PGE2 was added to smooth muscle cells to observe downstream cAMP and PKA changes., Results: The expression of EP2 and EP4 proteins in ureteral smooth muscle was verified by Western blot analysis. According to immunofluorescence, EP2 was primarily found on the cell membrane, while EP4 was found in the nucleus. In vitro, PGE2 induced concentration-dependent ureteral relaxation. Maximum diastolic rate was 70.94 ± 4.57% at a concentration of 30µM. EP2 antagonists hindered this effect, while EP4 antagonists did not. Obstructed ureters exhibited elevated mPGES-1 and EP2 protein expression (P < 0.01). Smooth muscle cells treated with PGE2 displayed increased cAMP and phosphorylated PKA., Conclusions: PGE2 binding to EP2 induces ureteral relaxation through the cAMP-PKA pathway. This will provide a new theoretical basis for the development of new therapeutic approaches for the use of PGE2 in the treatment of ureteral stones., (© 2024. The Author(s).)

Objective: To examine the effects of Jacobson's Progressive Muscle Relaxation Technique (JPMRT) on menstrual pain and symptoms, anxiety, quality of life (QoL), social activity, and work/school performance in primary dysmenorrhea (PD)., Materials and Methods: Women with PD were randomly divided into two groups as relaxation and control groups. JPMRT was applied three times a week from the estimated date of ovulation to the onset of the next menstruation. No treatment was performed in the control group. Pain intensity, menstrual symptoms, anxiety, impacts on QoL, social activity, and work/school performance were assessed before and after the interventions., Results: After the interventions, there was a further decrease in menstrual pain intensity, menstrual symptoms, anxiety level, the impact of QoL, and the work/school performance scores in the relaxation group than in the control group (p < 0.05)., Conclusion: JPMRT might be used as an alternative method in the treatment of PD., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Purines such as ATP are regulatory transmitters in motility of the gastrointestinal tract. The aims of this study were to propose functional roles of purinergic regulation of esophageal motility. An isolated segment of the rat esophagus was placed in an organ bath, and mechanical responses were recorded using a force transducer. Exogenous application of ATP (10-100 μM) evoked relaxation of the esophageal smooth muscle in a longitudinal direction under the condition of carbachol (1 μM) -induced precontraction. Pretreatment with a non-selective P2 receptor antagonist, suramin (500 μM), and a P2Y receptor antagonist, cibacron blue F3GA (200 μM), inhibited the ATP (100 μM) -induced relaxation, but a P2X receptor antagonist, pyridoxal phosphate-6-azophenyl-2,4-disulfonic acid (50 μM), did not affect it. A blocker of ATP-dependent potassium channels (K ATP channels), glibenclamide (200 μM), inhibited the ATP-induced relaxation and application of an opener of K ATP channels, nicorandil (50 μM), produced relaxation. The findings suggest that ATP is involved in inhibitory regulation of the longitudinal smooth muscle in the muscularis mucosae of the rat esophagus via activation of P2Y receptors and then opening of K ATP channels., (© 2024. The Author(s).)

Purpose: During alternate movements across a joint, the changeover from one direction of rotation to the opposite may be influenced by the delay and rate of tension reduction and the compliance to re-lengthening of the previously active muscle group. Given the aging process may affect the above-mentioned factors, this work aimed to compare the dynamics of both the ankle torque decline and muscle re-lengthening, mirrored by mechanomyogram (MMG), in the tibialis anterior because of its important role in gait., Methods: During the relaxation phase, after a supramaximal 35 Hz stimulation applied at the superficial motor point, in 20 young (Y) and 20 old (O) subjects, the torque (T) and MMG dynamics characteristics were measured., Results: The T and MMG analysis provided: (I) the beginning of the decay after cessation of stimulation (T: 22.51 ± 5.92 ms [Y] and 51.35 ± 15.21 ms [O]; MMG: 27.38 ± 6.93 ms [Y] and 61.41 ± 18.42 ms [O]); (II) the maximum rate of reduction (T: - 110.4 ± 45.56 Nm/s [Y] and - 52.72 ± 32.12 Nm/s [O]; MMG: - 24.47 ± 10.95 mm/s [Y] and - 13.76 ± 6.54 mm/s [O]); (III) the muscle compliance, measuring the MMG reduction of every 10% reduction of torque (bin 20-10%: 15.69 ± 7.5[Y] and 10.8 ± 3.3 [O]; bin 10-0%: 22.12 ± 10.3 [Y] and 17.58 ± 5.6 [O])., Conclusion: Muscle relaxation results are different in Y and O and can be monitored by a non-invasive method measuring physiological variables of torque and re-lengthening dynamics at the end of the electromechanical coupling previously induced by the neuromuscular stimulation., (© 2023. The Author(s).)

Impaired muscle relaxation is a notable feature in specific myopathies. Transcranial magnetic stimulation (TMS) of the motor cortex can induce muscle relaxation by abruptly halting corticospinal drive. Our aim was to quantify muscle relaxation using TMS in different myopathies with symptoms of muscle stiffness, contractures/cramps, and myalgia and explore the technique's diagnostic potential. In men, normalized peak relaxation rate was lower in Brody disease (n = 4) (-3.5 ± 1.3 s -1 ), nemaline myopathy type 6 (NEM6; n = 5) (-7.5 ± 1.0 s -1 ), and myotonic dystrophy type 2 (DM2; n = 5) (-10.2 ± 2.0 s -1 ) compared to healthy (n = 14) (-13.7 ± 2.1 s -1 ; all P ≤ 0.01) and symptomatic controls (n = 9) (-13.7 ± 1.6 s -1 ; all P ≤ 0.02). In women, NEM6 (n = 5) (-5.7 ± 2.1 s -1 ) and McArdle patients (n = 4) (-6.6 ± 1.4 s -1 ) had lower relaxation rate compared to healthy (n = 10) (-11.7 ± 1.6 s -1 ; both P ≤ 0.002) and symptomatic controls (n = 8) (-11.3 ± 1.8 s -1 ; both P ≤ 0.008). TMS-induced muscle relaxation achieved a high level of diagnostic accuracy (area under the curve = 0.94 (M) and 0.92 (F)) to differentiate symptomatic controls from myopathy patients. Muscle relaxation assessed using TMS has the potential to serve as a diagnostic tool, an in-vivo functional test to confirm the pathogenicity of unknown variants, an outcome measure in clinical trials, and monitor disease progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nens van Alfen performs editorial services for Wiley Publishing Inc; payment goes to their employer., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical G βγ -mediated stimulation of Ca 2+ release from intracellular stores by activation of PLCβ (phospholipase Cβ). Alone, this [Ca 2+ ] i signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at G q -coupled receptors also increase [Ca 2+ ] i . We established that TAS2R14 activation in HASM promotes relaxation through F-actin (filamentous actin) severing. This destabilization of actin was from agonist-promoted activation (dephosphorylation) of cofilin, which was pertussis toxin sensitive. Cofilin dephosphorylation was due to TAS2R-mediated deactivation of LIM domain kinase. The link between early receptor action and the distal cofilin dephosphorylation was found to be the polarity protein partitioning defective 3 (Par3), a known binding partner with PLCβ that inhibits LIM kinase. The physiologic relevance of this pathway was assessed using knock-downs of cofilin and Par3 in HASM cells and in human precision-cut lung slices. Relaxation by TAS2R14 agonists was ablated with knock-down of either protein as assessed by magnetic twisting cytometry in isolated cells or intact airways in the slices. Blocking [Ca 2+ ] i release by TAS2R14 inhibited agonist-promoted cofilin dephosphorylation, confirming a role for [Ca 2+ ] i in actin-modifying pathways. These results further elucidate the mechanistic basis of TAS2R-mediated HASM relaxation and point toward nodal points that may act as asthma or chronic obstructive pulmonary disease response modifiers or additional targets for novel bronchodilators.

Background: Among the main methods used to identify an altered flexion relaxation phenomenon (FRP) in nonspecific chronic low back pain (NSCLBP), it has been previously demonstrated that flexion relaxation ratio (FRR) and extension relaxation ratio (ERR) are more objective than the visual reference method., Objective: To determine the sensitivity and specificity of the different methods used to calculate the ratios in terms of their ability to identify an altered FRP in NSCLBP., Methods: Forty-four NSCLBP patients performed a standing maximal trunk flexion task. Surface electromyography (sEMG) was recorded along the erector spinae longissimus (ESL) and multifidus (MF) muscles. Altered FRP based on sEMG was visually identified by three experts (current standard). Six FRR methods and five ERR methods were used both for the ESL and MF muscles. ROC curves (with areas under the curve (AUC) and sensitivity/specificity) were generated for each ratio., Results: All methods used to calculate these ratios had an AUC higher than 0.9, excellent sensitivity (>90 %), and good specificity (80-100 %) for both ESL and MF muscles., Conclusion: Both FRP ratios (FRR and ERR) for MF and ESL muscles, appear to be an objective, sensitive and specific method for identifying altered FRP in NSCLBP patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Transcranial magnetic stimulation (TMS) of the motor cortex can be used during a voluntary contraction to inhibit corticospinal drive to the muscle and consequently induce involuntary muscle relaxation. Our aim was to evaluate the reproducibility and the effect of varying experimental conditions (robustness) of TMS-induced muscle relaxation. Relaxation of deep finger flexors was assessed in 10 healthy subjects (5 M, 5 F) using handgrip dynamometry with normalized peak relaxation rate as main outcome measure, that is, peak relaxation rate divided by (voluntary plus TMS-evoked)force prior to relaxation. Both interday and interrater reliability of relaxation rate were high with intraclass correlation coefficient of 0.88 and 0.92 and coefficient of variation of 3.8 and 3.7%, respectively. Target forces of 37.5% of maximal voluntary force or higher resulted in similar relaxation rate. From 50% of maximal stimulator output and higher relaxation rate remained the same. Only the most lateral position (>2 cm from the vertex) rendered lower relaxation rate (mean ± SD: 11.1 ± 3.0 s -1 , 95% CI: 9.0-13.3 s -1 ) compared to stimulation at the vertex (12.8 ± 1.89 s -1 , 95% CI: 11.6-14.1 s -1 ). Within the range of baseline skin temperatures, an average change of 0.5 ± 0.2 s -1 in normalized peak relaxation rate was measured per 1°C change in skin temperature. In conclusion, interday and interrater reproducibility and reliability of TMS-induced muscle relaxation of the finger flexors were high. Furthermore, this technique is robust with limited effect of target force, stimulation intensity, and coil position. Muscle relaxation is strongly affected by skin temperature; however, this effect is marginal within the normal skin temperature range. We deem this technique well suited for clinical and scientific assessment of muscle relaxation., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

In this study, we investigated the possible role of the l-cysteine/hydrogen sulfide pathway in β 3 -adrenoceptors-mediated relaxation in isolated mouse gastric fundus tissue. l-cysteine (endogenous H 2 S; 10 -6 -10 -2  M), sodium hydrogen sulfide (NaHS; exogenous H 2 S; 10 -6 -10 -3  M), selective β 3 -adrenoceptors agonist BRL 37344 (10 -9 -10 -4  M) and non-selective β-adrenoceptor agonist isoprenaline (10 -9 -10 -4  M) produced concentration-dependent relaxation in mouse gastric fundus. The non-selective β-adrenoceptors antagonist propranolol (10 -6  M) inhibited the relaxant response to isoprenaline but not to BRL 37344. On the other hand, the selective β 3 -adrenoceptors antagonist SR 59230A (10 -5  M) inhibited the relaxant responses to BRL 37344. In addition, cystathionine-gamma-lyase (CSE) inhibitor D,L-propargylglycine (PAG, 10 -2  M), cystathionine-beta-synthase inhibitor (CBS) aminooxyacetic acid (AOAA, 10 -2  M), and the combination of these inhibitors significantly reduced the relaxant responses induced by l-cysteine and BRL 37344. Pre-incubation of gastric fundal strips with propranolol (10 -6  M) and SR 59230A (10 -5  M) did not affect relaxations to l-cysteine and NaHS. Also, the existence of CSE, CBS, 3-mercaptopurivate sulfur transferase (3-MST) enzymes and β 3 -adrenoceptors were detected in gastric fundal tissue. Furthermore, basal H 2 S release was detected in the measurements. H 2 S level increased in the presence of l-cysteine, NaHS, and BRL 37344. The increase in H 2 S level by l-cysteine and BRL 37344 decreased significantly with PAG and AOAA enzyme inhibitors. These results suggest that endogenous H 2 S is synthesized from l-cysteine at least by CBS and CSE enzymes. Also, β 3 -adrenoceptors are found in the mouse stomach fundus and mediate BRL 37344-induced relaxations, and l-cysteine/hydrogen sulfide pathway plays a partial role in β 3 -adrenoceptors-mediated relaxation in mouse gastric fundus tissue., (Copyright © 2021. Published by Elsevier Inc.)

In most living cells, the second-messenger roles for adenosine 3',5'-cyclic monophosphate (cAMP) are short-lived, confined to the intracellular space, and tightly controlled by the binary switch-like actions of Gα s (stimulatory G protein)-activated adenylyl cyclase (cAMP production) and cAMP-specific PDE (cAMP breakdown). Here, by using human airway smooth muscle (HASM) cells in culture as a model, we report that activation of the cell-surface β 2 AR (β 2 -adrenoceptor), a G s -coupled GPCR (G protein-coupled receptor), evokes cAMP egress to the extracellular space. Increased extracellular cAMP levels ([cAMP] e ) are long-lived in culture and are induced by receptor-dependent and receptor-independent mechanisms in such a way as to define a universal response class of increased intracellular cAMP levels ([cAMP] i ). We find that HASM cells express multiple ATP-binding cassette (ABC) membrane transporters, with ABCC1 (ABC subfamily member C 1) being the most highly enriched transcript mapped to MRPs (multidrug resistance-associated proteins). We show that pharmacological inhibition or downregulation of ABCC1 with siRNA markedly reduces β 2 AR-evoked cAMP release from HASM cells. Furthermore, inhibition of ABCC1 activity or expression decreases basal tone and increases β-agonist-induced HASM cellular relaxation. These findings identify a previously unrecognized role for ABCC1 in the homeostatic regulation of [cAMP] i in HASM that may be conserved traits of the G s -GPCRs (G s -coupled family of GPCRs). Hence, the general features of this activation mechanism may uncover new disease-modifying targets in the treatment of airflow obstruction in asthma. Surprisingly, we find that serum cAMP levels are elevated in a small cohort of patients with asthma as compared with control subjects, which warrants further investigation.

The interstitial cells of Cajal (ICCs) play an important role in coordinated gastrointestinal motility. The present study aimed to elucidate whether or how ICCs are involved in the lower esophageal sphincter (LES) relaxation induced by stimulation of the nicotinic acetylcholine receptor. The application of 1,1-dimethyl-4-phenyl-piperazinium (DMPP; a nicotinic acetylcholine receptor agonist) induced a transient relaxation in the circular smooth muscle of the porcine LES. DMPP-induced relaxation was abolished by not only 1 μM tetrodotoxin but also the inhibition of ICC activity by pretreatment with 100 μM carbenoxolone (a gap junction inhibitor), pretreatment with 100 μM CaCCinh-A01 (an anoctamin-1 blocker acting as a calcium-activated chloride channel inhibitor), and pretreatment with Cl - -free solution. However, pretreatment with 100 μM N ω -nitro-L-arginine methyl ester had little effect on DMPP-induced relaxation. Furthermore, DMPP-induced relaxation was inhibited by pretreatment with 1 mM suramin, a purinergic P2 receptor antagonist, but not by 1 μM VIP (6-28), a vasoactive intestinal peptide (VIP) receptor antagonist. Stimulation of the purinergic P2 receptor with adenosine triphosphate (ATP) induced relaxation, which was abolished by the inhibition of ICC activity by pretreatment with CaCCinh-A01. In conclusion, membrane hyperpolarization of the ICCs via the activation of anoctamin-1 plays a central role in DMPP-induced relaxation. ATP may be a neurotransmitter for inhibitory enteric neurons, which stimulate the ICCs. The ICCs act as the interface of neurotransmission of nicotinic acetylcholine receptor in order to induce LES relaxation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Asthma affects millions of people worldwide and its prevalence is increasing. It is characterized by chronic airway inflammation, airway remodeling, and pathologic bronchoconstriction, and it poses a continuous treatment challenge with very few new therapeutics available. Thus, many asthmatics turn to plant-based complementary products, including ginger, for better symptom control, indicating an unmet need for novel therapies. Previously, we demonstrated that 6-shogaol (6S), the primary bioactive component of ginger, relaxes human airway smooth muscle (hASM) likely by inhibition of phosphodiesterases (PDEs) in the β-adrenergic (cyclic nucleotide PDEs), and muscarinic (phospholipase C, PLC) receptor pathways. However, oral 6S is extensively metabolized and it is unknown if the resulting metabolites remain bioactive. Here, we screened all the known human metabolites of 6S and several metabolite-based synthetic derivatives to better understand their mechanism of action and structure-function relationships. We demonstrate that several metabolites and metabolite-based synthetic derivatives are able to prevent Gq-coupled stimulation of intracellular calcium [Ca 2+ ] i and inositol trisphosphate (IP 3 ) synthesis by inhibiting PLC, similar to the parent compound 6S. We also show that these compounds prevent recontraction of ASM after β-agonist relaxation likely by inhibiting PDEs. Furthermore, they potentiate isoproterenol-induced relaxation. Importantly, moving beyond cell-based assays, metabolites also retain the functional ability to relax Gq-coupled-contractions in upper (human) and lower (murine) airways. The current study indicates that, although oral ginger may be metabolized rapidly, it retains physiological activity through its metabolites. Moreover, we are able to use naturally occurring metabolites as inspiration to develop novel therapeutics for brochoconstrictive diseases.

It is known that nitric oxide (NO) plays a key physiological role in the control of gastrointestinal (GI) motor phenomena. In this respect, NO is considered as the main non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter responsible for smooth muscle relaxation. Moreover, many substances (including hormones) have been reported to modulate NO production leading to changes in motor responses, further underlying the importance of this molecule in the control of GI motility. An impaired NO production/release has indeed been reported to be implicated in some GI dysmotility. In this article we wanted to focus on the influence of NO on gastric motility by summarizing knowledge regarding its role in both physiological and pathological conditions. The main role of NO on regulating gastric smooth muscle motor responses, with particular reference to NO synthases expression and signaling pathways, is discussed. A deeper knowledge of nitrergic mechanisms is important for a better understanding of their involvement in gastric pathophysiological conditions of hypo- or hyper-motility states and for future therapeutic approaches. A possible role of substances which, by interfering with NO production, could prove useful in managing such motor disorders has been advanced.

Objective: To test the effects of hot-water immersion on the rapid force production and parameters of neuromuscular function in healthy adults., Design: Cross-sectional study., Methods: Fifteen healthy adults (24.9±5.6 years; 178±11.4cm; 72.8±16.2kg) performed neuromuscular assessments before, after and ∼15min after either 90min of 42°C (hot) or 36°C (sham-condition) water immersion (lower body). Knee extensors rate of torque development (RTD) was measured during explosive voluntary contraction in the interval of 0-50ms (RTD V50 ) and 0-150ms (RTD V150 ) and during electrically-evoked contractions by single twitches (RTD twitch ) and low- and high-frequencies doublets (RTD 20Hz and 100Hz ). Rate of EMG rise (RER) was calculated for voluntary contractions and half-relaxation time (HRT) and electromechanical delay (EMD) was measured during single twitches., Results: After the hot-water immersion (when rectal and muscle temperature were elevated [↑1°C and ↑2.4°C, respectively]), RTD V50 , RTD 20Hz and RTD 100Hz significantly increased and HRT decreased when compared to baseline and sham-condition (p<0.05). Approximately 15min after the hot-water immersion (when muscle temperature was still higher [↑1.4°C], but rectal temperature at baseline level), RTD V50 remained higher and RTD twitch presented higher values than baseline and sham-condition. The RTD 20Hz and RTD 100Hz showed further increases compared to post hot-water immersion trials. HRT showed no changes compared to post water immersion, but the EMD presented lower values than baseline and sham-condition. No changes were observed for RTD V150 and RER at any moment., Conclusion: Increased muscle temperature provoked by 42°C hot-water immersion increases the early phase of the RTD (<70ms) (voluntary and evoked) and decreases HRT and EMD of the knee extensors., (Copyright © 2021 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Muscle fatigue is a complex phenomenon enclosing various mechanisms. Despite technological advances, these mechanisms are still not fully understood in vivo. Here, simultaneous measurements of pressure, volume, and ribcage inspiratory muscle activity were performed non-invasively during fatigue (inspiratory threshold valve set at 70% of maximal inspiratory pressure) and recovery to verify if inspiratory ribcage muscle fatigue (1) leads to slowing of contraction and relaxation properties of ribcage muscles and (2) alters median frequency and high-to-low frequency ratio (H/L). During the fatigue protocol, sternocleidomastoid showed the fastest decrease in median frequency and slowest decrease in H/L. Fatigue was also characterized by a reduction in the relative power of the high-frequency and increase of the low-frequency. During recovery, changes in mechanical power were due to changes in shortening velocity with long-lasting reduction in pressure generation, and slowing of relaxation [i.e., tau (τ), half-relaxation time (½RT), and maximum relaxation rate (MRR)] was observed with no significant changes in contractile properties. Recovery of median frequency was faster than H/L, and relaxation rates correlated with shortening velocity and mechanical power of inspiratory ribcage muscles; however, with different time courses. Time constant of the inspiratory ribcage muscles during fatigue and recovery is not uniform (i.e., different inspiratory muscles may have different underlying mechanisms of fatigue), and MRR, ½RT, and τ are not only useful predictors of inspiratory ribcage muscle recovery but may also share common underlying mechanisms with shortening velocity.

Typical patterned movements in animals are achieved through combinations of contraction and delayed relaxation of groups of muscles. However, how intersegmentally coordinated patterns of muscular relaxation are regulated by the neural circuits remains poorly understood. Here, we identify Canon, a class of higher-order premotor interneurons, that regulates muscular relaxation during backward locomotion of Drosophila larvae. Canon neurons are cholinergic interneurons present in each abdominal neuromere and show wave-like activity during fictive backward locomotion. Optogenetic activation of Canon neurons induces relaxation of body wall muscles, whereas inhibition of these neurons disrupts timely muscle relaxation. Canon neurons provide excitatory outputs to inhibitory premotor interneurons. Canon neurons also connect with each other to form an intersegmental circuit and regulate their own wave-like activities. Thus, our results demonstrate how coordinated muscle relaxation can be realized by an intersegmental circuit that regulates its own patterned activity and sequentially terminates motor activities along the anterior-posterior axis.

Objectives: Dysfunctions in the lower esophageal sphincter (LES) and the upper esophageal sphincter (UES) levels can occur owing to poor muscle coordination, contraction, or relaxation. Such condition can possibly be addressed by functional rehabilitation. The aim of this study was to measure pressure changes in the UES and LES at rest and during routine rehabilitation techniques, that is, cervical manual traction and trunk stabilization maneuver., Methods: This study was conducted in a University Hospital Gastrointestinal Endoscopy Center. Cervical manual traction and a trunk stabilization maneuver were performed in a convenient group of 54 adult patients with gastroesophageal reflux disease. High-resolution manometry was used to measure pressure changes in the LES and UES at rest and during manual cervical traction and trunk stabilization maneuver., Results: Average initial resting UES pressure was 90.91 mmHg. A significant decrease was identified during both cervical traction (average UES pressure = 42.13 mmHg, P < .001) and trunk stabilization maneuver (average UES pressure = 62.74 mmHg, P = .002). The average initial resting LES pressure was 14.31 mmHg. A significant increase in LES pressure was identified both during cervical traction (average LES pressure = 21.39 mmHg, P < .001) and during the trunk stabilization maneuver, (average pressure = 24.09 mmHg, P < .001)., Conclusion: Cervical traction and trunk stabilization maneuvers can be used to decrease pressure in the UES and increase LES pressure in patients with gastroesophageal reflux disease., (Copyright © 2021. Published by Elsevier Inc.)

The preparatory accommodation response of lower esophageal sphincter (LES) before swallowing is one of the mechanisms involved in LES relaxation during wet swallows, however, the physiological and/or pathological roles of LES accommodation remain to be determined in humans. To address this problem, we conducted a prospective observational study of 38 patients with normal high-resolution manometry (HRM) and 23 patients with idiopathic esophagogastric junction outflow obstruction (EGJOO) to assess dry and wet swallows. The LES accommodation measurement was proposed for practical use in evaluating the LES accommodation response. Although swallow-induced LES relaxation was observed in both dry and wet swallows, LES accommodation (6.4, 3.1-11.1 mmHg) was only observed in wet swallows. The extent of LES accommodation was impaired in idiopathic EGJOO (0.6, - 0.6-6 mmHg), and the LES accommodation measurement of patients with idiopathic EGJOO (36.8, 29.5-44.3 mmHg) was significantly higher in comparison to those with normal HRM (23.8, 18-28.6 mmHg). Successful LES relaxation in wet swallowing can be achieved by LES accommodation in combination with swallow-induced LES relaxation. Impaired LES accommodation is characteristic of idiopathic EGJOO. In addition to the IRP value, the LES accommodation measurement may be useful for evaluating the LES relaxation function in clinical practice.

Background: The mechanisms associated with gastro-esophageal reflux (GER) episodes were studied using combined High-resolution Impedance Manometry (HRIM) and pH monitoring in ambulant subjects with different patterns of GERD., Methods: Sixteen subjects with mild-moderate esophagitis (Los Angeles (LA) grade A&B) (group A) and 11 subjects with severe esophagitis (LA grade C&D) or Barrett's esophagus (BE) were studied before and after a meal, resting, while walking, and during standardized exercise, using a HRIM and a pH probe., Key Results: Post-prandial acid GER episodes were more common in group B (median 10 range (3-18) vs A (6.5 (0-18), p = 0.048). Postprandial acid clearance time was much longer in group B (median 0.71( 0.07-2.66 min) vs A (0.17 (0.04-2.44 min), p = 0.02). Transient lower esophageal sphincter relaxation (TLESR) was the most frequent mechanism associated with GER episodes in both groups. Post-prandial TLESRs with GER were more common in group B (median 17 (9-24) vs A 13.5 (7-34), p = 0.014), particularly during exercise (B 8 (6-9) vs A 6 (5-6.8), p = 0.007). Post-prandially TLESR with acid reflux increased during exercise in both groups (A rest median 2.4 (0-6.4) per hour vs exercise 4.7 (0-17.3), p = 0.005 and B 4 (0.8-9.6) vs 5.3 (2.7-13.3) per hour, p = 0.045)., Conclusions and Inferences: TLESR was the most common mechanism associated with reflux episodes in all subjects. Acid reflux episodes were more common in subjects with severe esophagitis or BE and esophageal acid clearance was much slower. Post-prandial exercise increased TLESR with acid reflux and GERD patients should be encouraged to avoid exercise immediately after a meal., (© 2020 John Wiley & Sons Ltd.)

Background: Altered inter-joint coordination and reduced flexion-relaxation at end-range trunk flexion are common in people with low back pain. Inconsistencies in these behaviors, however, make assessment and treatment challenging for this population., Research Question: The study objective was to investigate patterns of regional lumbo-pelvic coordination and flexion-relaxation in adults with and without low back pain, during a bending task., Methods: Adults with low back pain (n = 16) and a healthy group (n = 21) performed three trials of a bending task. Motion capture and surface electromyography systems measured joint kinematics (hip, lower and upper lumbar spine) and muscle activity (erector spinae longissimus, iliocostalis, and multifidus). Continuous relative phase analysis determined inter-joint coordination of the hip/lower lumbar and lower lumbar/upper lumbar joint pairs, during flexion and extension periods. Flexion-relaxation ratios using normalized surface electromyography data determined the extent of flexion-relaxation for each muscle, during each period. For inter-joint coordination, two-way repeated measure mixed ANOVAs calculated the effects of group (healthy/low back pain), period, and their interactions. Separate hierarchical linear models were constructed and tested relationships between flexion-relaxation ratios and our independent variables, group and muscle, while controlling for patient characteristics., Results: The low back pain group had more out-of-phase coordination of the hip/lower lumbar joint pair compared to the healthy group (mean difference = 24.7°; 95 % confidence interval = 3.93-45.4), independent of movement period. No significant between group differences in lower lumbar/upper lumbar coordination were observed. The low back pain group demonstrated reduced flexion-relaxation of all muscles during full flexion (21.7 % reduction on average), with multifidus showing the least relaxation., Significance: Regional differences in the lumbar spine and the possibility of subgroups with distinct movement pattern should be considered when analyzing coordination in people with low back pain. Multifidus showed the largest changes in flexion-relaxation and should be included when measuring this construct., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Robert Furchgott was first noted for research on drug-receptor theory, autonomic neuroeffector mechanisms, and vascular pharmacology/physiology. His studies on drug-receptor interactions provided important knowledge about the properties of drug receptors long before methodologies were developed to study them directly. However, Furchgott achieved an enduring legacy for recognizing the importance of endothelial cells for the relaxation of vascular smooth muscle. On the basis of his own experiments and those of others, he proposed that acetylcholine interacted with muscarinic receptors at the surface of endothelial cells to release a substance called endothelium relaxing factor. Endothelium relaxing factor was later identified as nitric oxide, a colorless, odorless gas. Furchgott's discovery of an entirely new mechanism by which blood vessels dilate revolutionized studies on the physiology of the vascular system. His work also suggested new treatments for hypertension and heart disease, and was a key factor in the development of the anti-impotence drug sildenafil. In 1998, Robert Furchgott shared the Nobel Prize in Physiology or Medicine with Ferid Murad and Louis Ignarro.

Recently, we characterized blue light-mediated relaxation (photorelaxation) of airway smooth muscle (ASM) and implicated the involvement of opsin 3 (OPN3), an atypical opsin. In the present study, we characterized the cellular signaling mechanisms of photorelaxation. We confirmed the functional role of OPN3 in blue light photorelaxation using trachea from OPN3 null mice (maximal relaxation 52 ± 13% compared with wild-type mice 90 ± 4.3%, P  < 0.05). We then demonstrated colocalization of OPN3 and G α s using co-IP and proximity ligation assays in primary human ASM cells, which was further supported by an increase in cAMP in mouse trachea treated with blue light compared with dark controls (23 ± 3.6 vs. 14 ± 2.6 pmol cAMP/ring, P  < 0.05). Downstream PKA (protein kinase A) involvement was shown by inhibiting photorelaxation using Rp-cAMPS ( P  < 0.0001). Moreover, we observed converging mechanisms of desensitization by chronic β 2 -agonist exposure in mouse trachea and correlated this finding with colocalization of OPN3 and GRK2 (G protein receptor kinase) in primary human ASM cells. Finally, an overexpression model of OPN1LW (a red light photoreceptor in the same opsin family) in human ASM cells showed an increase in intracellular cAMP levels following red light exposure compared with nontransfected cells (48 ± 13 vs. 13 ± 2.1 pmol cAMP/mg protein, P  < 0.01), suggesting a conserved photorelaxation mechanism for wavelengths of light that are more tissue penetrant. Together, these results demonstrate that blue light photorelaxation in ASM is mediated by the OPN3 receptor interacting with G α s , which increases cAMP levels, activating PKA and modulated by GRK2.

We investigated the vascular response to nucleobase adenine using freshly isolated superior mesenteric arteries of spontaneously hypertensive rats (SHR) and its control, Wistar Kyoto (WKY) rats. Endothelium-dependent and endothelium-independent relaxations were assessed in isolated segments in an organ bath. The releases of the metabolites of thromboxane A 2 and prostaglandin I 2 were also detected. Adenine induced vasorelaxation in both the endothelium-intact and endothelium-denuded arteries in a concentration-dependent manner. In the SHR group, the adenine-induced relaxation was slightly but significantly reduced in the endothelium-intact rings when compared with that in the WKY group. However, the relaxation in the endothelium-denuded rings were similar between the two groups. The difference in the adenine-mediated relaxation in the superior mesenteric arteries between the SHR and WKY groups was eliminated by endothelial denudation and a nitric oxide (NO) synthase inhibitor. In the absence and presence of adenine, SHR tended to have higher levels of metabolites of thromboxane A 2 and prostaglandin I 2 compared with WKY. However, adenine did not induce the release of these substances in the arteries in both the SHR and WKY groups. These results suggest that the reduced adenine-mediated relaxation in the superior mesenteric arteries in SHR is due to a lack of contribution from the endothelium-derived NO and not from the release of prostanoids.

Sun, M-Y, Lu, J-Q, Ma, Z-C, Lü, J-J, Huang, Q, Sun, Y-N, and Liü, Y. Effects of the inertia barbell training on lumbar muscle T2 relaxation time. J Strength Cond Res 34(12): 3454-3462, 2020-The purpose of this study was to investigate variations in T2 relaxation time in normal human lumbar muscles caused by inertia barbell training. Thirty undergraduate healthy men (mean age = 19 ± 1.2 years, body mass = 72 ± 10.0 kg, and height = 1.78 ± 0.1 m) were recruited to participate in this study. Subjects were randomly assigned into 2 groups: an inertia barbell training group (IBTG) (n = 15) and a normal barbell-training group (NBTG) (n = 15). All subjects participated in lumbar flexion and extension muscle strength training for 1 hour per time, 3 times per week for a total of 8 weeks. The lumbar area of each subject was scanned before and after the experiment using a 3.0T superconductive magnetic resonance imaging system. The T2 values measured after intervention were significantly different compared with the T2 values measured before the experiment in both the IBTG and NBTG groups (p < 0.001). After intervention, there was no significant difference in T2 values between the IBTG and NBTG groups (p = 0.17). The ([INCREMENT]T2)/T2 percentage was significantly different in the IBTG group (p < 0.01). This study demonstrated that 8 weeks of strength training led to significant improvements in the values for T2 relaxation time of the lumbar muscles. Furthermore, the ([INCREMENT]T2)/T2 percentage for IBTG was higher than that for NBTG, which suggested that lumbar muscle activity increased more with inertial barbell training.

Bronchomotor tone is regulated by contraction and relaxation of airway smooth muscle (ASM). A weakened ASM relaxation might be a cause of airway hyperresponsiveness (AHR), a characteristic feature of bronchial asthma. Pituitary adenylyl cyclase-activating polypeptide (PACAP) is known as a mediator that causes ASM relaxation. To date, whether or not the PACAP responsiveness is changed in asthmatic ASM is unknown. The current study examined the hypothesis that relaxation induced by PACAP is reduced in bronchial smooth muscle (BSM) of allergic asthma. The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, the main bronchial smooth muscle (BSM) tissues were isolated. Tension study showed a BSM hyperresponsiveness to acetylcholine in the OA-challenged mice. Both quantitative RT-PCR and immunoblot analyses revealed a significant decrease in PAC 1 receptor expression in BSMs of the diseased mice. Accordingly, in the antigen-challenged group, the PACAP-induced PAC 1 receptor-mediated BSM relaxation was significantly attenuated, whereas the relaxation induced by vasoactive intestinal polypeptide was not changed. These findings suggest that the relaxation induced by PACAP is impaired in BSMs of experimental asthma due to a downregulation of its binding partner PAC 1 receptor. Impaired BSM responsiveness to PACAP might contribute to the AHR in asthma.

While acetylcholine is regarded to be the main directly contractile transmitter substance in the urinary bladder, interactions with other transmitters likely occur. Presently, the interplay between purinergic and cholinergic signalling was investigated to unravel the involvement of the urothelium and efferent neurons in the functionally important purinergically evoked release of acetylcholine in vitro. Functional characterization of receptor subtypes involved in this interplay was also performed. In vitro organ bath experiments with electrical field stimulation (EFS) or administration of agonist were performed in the absence and presence of the neurotoxin tetrodotoxin (TTX; 5 × 10 -7  M) and/or receptor antagonists, in intact and urothelium-denuded full thickness rat bladder strip preparations. Interestingly, functional contractions to ATP (10 -6 -10 -3  M) remained unaffected by TTX, but were significantly lowered in the presence of the muscarinic antagonist atropine (10 -6  M). However, in urothelium-denuded strip preparations, this latter phenomenon was not present and the ATP response remained unaltered. To rule out purinergic interference caused by break-down of ATP, experiments were performed in which the stable ATP-analogue αβMeATP (10 -7 -10 -5  M) gave rise to functional atropine-sensitive contractions. Furthermore, contractions to ATP were not affected by P2Y6 purinoceptor blockade (by MRS2578; 10 -7 , 10 -5  M), nor were relaxatory responses to ATP sensitive to atropine, PPADS (3 × 10 -5  M) or αβMeATP. Lastly, relaxations to ADP (10 -6 -10 -3  M) or NECA (10 -8 -10 -5  M) were unaltered by the presence of atropine. To conclude, purinergic functional contractile, but not relaxatory, responses are supported by the cholinergic transmitter system in vitro, through non-neuronal mechanisms in the urothelium. Involved purinoceptors are of the P2X-subtype, most likely P2X1 and/or P2X3., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Spontaneous preterm birth (sPTB) remains a worldwide healthcare challenge. Preterm labor (PTL) is thought to be the largest reversible cause of sPTB, but current tocolytic therapies are ineffective and associated with systemic side effects from chronic use. Therefore, identifying novel mechanisms that promote human uterine smooth muscle (hUSM) relaxation is essential to improving clinical management of PTL. Here, we aimed to determine if an extraocular opsin receptor (OPN 3,4,5) system is expressed in pregnant hUSM and to characterize how photo-mediated relaxation of pre-contracting hUSM may be facilitated by external application of light. Translational studies were performed with hUSM from healthy late gestation patients (n = 8) and non-pregnant, similarly aged patients undergoing hysterectomy (n = 4). First, RT-PCR screened for mRNA coding for components of the classical extraocular light receptors (OPN 3,4,5). We found a restricted repertoire of opsin receptors (OPN3) expressed in pregnant hUSM tissue. Immunohistochemistry was performed to confirm protein expression. Pre-contracting late gestation hUSM strips were studied in functional organ bath studies to determine if photo-mediated relaxation is intensity or wavelength dependent. Functional organ bath studies revealed acute photo-mediated relaxation occurring in an intensity- and wavelength-dependent manner. Finally, coimmunoprecipitation of OPN3 with Gs following light activation suggests that a component of photo-relaxation occurs via G protein-coupled receptor machinery. This is the first report of light-mediated relaxation of pre-contracted human myometrium. Activation of endogenous light receptors on human myometrium may become a novel, non-invasive tocolytic strategy.

Electromyographic biofeedback (EMG-BF) therapy provides information on the state of contraction of the targeted muscles and relaxation of their antagonists, which can facilitate early active range of motion (RoM) after elbow surgery. Our aim in this study was to calculate the minimum detectable change (MDC) during EMG-BF therapy, initiated in the early postoperative period after elbow surgery.This study is an observational case series. EMG-BF of muscle contraction and relaxation was provided during active elbow flexion and extension exercises. Patients completed 3 sets of 10 trials each of flexion and extension over 4 weeks. The total range of flexion-extension motion and scores on the Japanese Society for Surgery of the Hand version of the disability of the arm, shoulder, and hand questionnaire and the Japanese version of the Patient-Rated Elbow Evaluation were obtained at baseline and weekly during the 4-week intervention period. A prediction formula was developed from the time-series data obtained during the intervention period, using the least-squares method. The estimated value was calculated by removing the slope from the prediction formula and adding the initial scores to residuals between the measured scores and predicted scores individually. Systematic error, MDC at the 95th percentile cutoff (MDC95), repeatability of the measures, and the change from the baseline to each time-point of intervention were assessed.The MDC95 was obtained for all 3 outcome measures and the range of values was as follows: RoM, 8.3° to 22.5°; Japanese version of the Patient-Rated Elbow Evaluation score, 17.6 to 30.6 points; and disability of the arm, shoulder, and hand questionnaire subscale: disability and symptoms score, 14.2 to 22.9 points.The efficacy of EMG-BF after elbow surgery was reflected in earlier initiation of elbow RoM after surgery and improvement in patient-reported upper limb function scores. The calculated MDC95 cut-offs could be used as reference values to assess the therapeutic effects of EMG-BF in individuals.

We analyzed the correlations between the T 2 shift and integrated electromyographic (iEMG) values in the masseter and temporal muscles. Six healthy adults engaged in a clenching task over two durations at various bite forces. We evaluated the mean T 2 shift per voxel and assessed their correlations with iEMG using a linear mixed model. The regression coefficients were different for each muscle type, similar for the left and right sides, and decreased upon doubling duration.

Control of the body requires inhibiting complex actions, involving contracting and relaxing muscles. However, little is known of how voluntary commands to relax a muscle are cancelled. Action inhibition causes both suppression of muscle activity and the transient excitation of antagonist muscles, the latter being termed active breaking. We hypothesized that active breaking is present when stopping muscle relaxations. Stop signal experiments were used to compare the mechanisms of active breaking for muscle relaxations and contractions in male and female human participants. In experiments 1 and 2, go signals were presented that required participants to contract or relax their biceps or triceps muscle. Infrequent Stop signals occurred after fixed delays (0-500 ms), requiring that participants cancelled go commands. In experiment 3, participants increased (contract) or decreased (relax) an existing isometric finger abduction depending on the go signal, and cancelled these force changes whenever Stop signals occurred (dynamically adjusted delay). We found that muscle relaxations were stopped rapidly, met predictions of existing race models, and had Stop signal reaction times that correlated with those observed during the stopping of muscle contractions, suggesting shared control mechanisms. However, stopped relaxations were preceded by transient increases in electromyography (EMG), while stopped contractions were preceded by decreases in EMG, suggesting a later divergence of control. Muscle state-specific active breaking occurred simultaneously across muscles, consistent with a central origin. Our results indicate that the later stages of action inhibition involve separate excitatory and inhibitory pathways, which act automatically to cancel complex body movements. SIGNIFICANCE STATEMENT The mechanisms of how muscle relaxations are cancelled are poorly understood. We showed in three experiments involving multiple effectors that stopping muscle relaxations involves transient bursts of EMG activity, which resemble cocontraction and have onsets that correlate with Stop signal reaction time. Comparison with the stopping of matched muscle contractions showed that active breaking was muscle state specific, being positive for relaxations and negative for contractions. The two processes were also observed to co-occur in agonist-antagonist pairs, suggesting separate pathways. The rapid, automatic activation of both pathways may explain how complex actions can be stopped at any stage of their execution., (Copyright © 2020 the authors.)

Striated muscle thick filaments are composed of myosin II and several non-myosin proteins. Myosin II's long α-helical coiled-coil tail forms the dense protein backbone of filaments, whereas its N-terminal globular head containing the catalytic and actin-binding activities extends outward from the backbone. Here, we report the structure of thick filaments of the flight muscle of the fruit fly Drosophila melanogaster at 7 Å resolution. Its myosin tails are arranged in curved molecular crystalline layers identical to flight muscles of the giant water bug Lethocerus indicus Four non-myosin densities are observed, three of which correspond to ones found in Lethocerus ; one new density, possibly stretchin-mlck, is found on the backbone outer surface. Surprisingly, the myosin heads are disordered rather than ordered along the filament backbone. Our results show striking myosin tail similarity within flight muscle filaments of two insect orders separated by several hundred million years of evolution., (© 2020 Daneshparvar et al.)

Objective: To define the role of the flexion-relaxation phenomenon (FRP), assessed through ratios (FRR), as a diagnostic test to define impairment in patients with chronic low back pain (CLBP)., Material and Method: The study sample consisted of 180 participants (16 healthy volunteers and 164 patients on work disability due to CLBP), who were consecutively referred for evaluation at the Biomechanics Laboratory of a workplace accident insurance company from January 2012 to December 2017. The evaluations consisted of an isometric dynamometry test, a kinematic test and assessment of the FRP phenomenon. Minimum criteria were established in the performance of the tests for their acceptance as valid for the study. Lumbar impairment or clinical recovery was defined on the basis of the results of the dynamometry and kinematic tests. The FRP response was assessed with FRRs. A total of 4 different ratios were taken for analysis with ROC curves., Results: A total of 86 valid tests were obtained (16 classified as lumbar impairment and 71 as recovered cases). The best ratio obtained an area under the ROC curve of 0.87, with a sensitivity of 0.84, a specificity of 0.87, and a positive predictive value of 97%., Conclusions: The FRP test, along with dynamometry and kinematic evaluations, is effective in identifying lumbar impairment and is the easiest test for patients with CLBP to perform., (Copyright © 2020 Sociedad Española de Rehabilitación y Medicina Física. Publicado por Elsevier España, S.L.U. All rights reserved.)

Pinto, BL and McGill, SM. Voluntary muscle relaxation can mitigate fatigue and improve countermovement jump performance. J Strength Cond Res 34(6): 1525-1529, 2020-When muscles contract, they create force and stiffness. Thus, muscle activation and relaxation must be strategically sequenced to coordinate and control movement, to enhance athletic variables such as speed and strength. However, research has favored investigation of muscle activation over relaxation. Athletes such as runners, swimmers, and boxers often shake their limbs to allow the muscle to oscillate freely, immediately before a bout. The purpose was to investigate whether shaking the lower limbs with the intention to voluntarily relax the muscles of the limb has an effect on countermovement jump (CMJ) performance. Subjects performed 10 maximal effort CMJs with 30 seconds of rest between each jump. During the rest period, they either performed the relaxation technique or control condition (standing still). Statistical significance was considered at p < 0.05. Subjects significantly improved jump height, compared with their first jump of the day, when performing the relaxation technique. To further investigate the mechanism of enhancement, subjects were grouped into responders and nonresponders. The responder group significantly decreased their jump height and concentric phase impulse (relative to the first jump) during the control condition compared with the nonresponder group, indicating fatigue. When performing the relaxation technique, the responder group improved their jump height and mitigated fatigue by significantly increasing their unweighting impulse and unweighting force. The relaxation technique improved CMJ performance, specifically in those that fatigue with consecutive bouts, by enhancing unweighting, that requires muscle relaxation, rather than propulsion that requires activation. This technique can be useful for training or competition.

When an individual enters a maximally flexed spine position, their largest extensor muscles become electrically inactive despite a substantial extensor moment demand being placed on the low back; this is termed flexion relaxation. Stresses within intervertebral discs, ligaments, and passive muscles are thought to support this moment thereby allowing the extensor muscles to 'turn off'. While the mechanical behaviour of the intervertebral disc and ligaments have been studied extensively, less is known regarding the moment supported by passive muscle tissue during spine flexion. Here we estimated the L4/L5 moment supported by the passive musculature during spine flexion based on experimentally derived architectural and material properties. We then tested the validity of the passive muscle prediction by determining whether the cumulative passive tissue moment (including passive muscle, intervertebral discs, and ligaments) would support the extensor moment demand-calculated with inverse dynamics-near maximum spine flexion. The model predicted that the passive tissues were able to support the entire extensor moment demand, indicating that muscle activity was not required to support the weight of the upper body, consistent with the mechanism of flexion relaxation. The model further demonstrated that despite being inactive, spine muscles still greatly contribute to flexion relaxation by passively supporting ~47% of the extensor moment demand on the spine. Finally, there was strong agreement between the predicted active muscle moments and the recorded spine muscle activity (EMG); this strong agreement persisted when the external moment was manipulated using a pulley-system. These findings provide additional confidence that the estimated passive muscle moments are reasonably accurate throughout spine flexion., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest associated with the work presented in this manuscript., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Major Depression is a stress-related disorder characterized by altered hypothalamic-pituitary-adrenal axis function. Mindfulness-based interventions have shown to improve subjective parameters of stress and to reduce relapse rates in depressed patients. However, research on their effects on diurnal patterns of cortisol and associations with subjective outcomes is lacking. The present Ambulatory Assessment study investigated possible changes in daily rhythm cortisol parameters (cortisol awakening response (CAR), daily slope, total cortisol) in currently remitted individuals with recurrent depression who were randomized to a four-week mindfulness-based focused attention training (MBAT, n = 39) or a progressive muscle relaxation training (PMR, n = 39). A second aim was to investigate whether changes in cortisol were linked to improvements in affective and cognitive daily life states. On three weekdays before and after the intervention, seven saliva cortisol samples per day were collected. For analysis, multilevel models were applied. Results revealed no group-specific or general change in CAR and daily slopes from pre- to postintervention. In contrast, total cortisol increased across groups, which was however moderated by group and subjective improvement status. While cortisol increased irrespective of subjective improvement in PMR participants, MBAT participants with larger reductions in negative affect and rumination maintained their initial cortisol levels, whereas those with lower improvement paralleled the PMR group. Thereby, MBAT appeared to buffer an increase in overall cortisol secretion over time, but only in patients showing marked improvements in those affective and cognitive states that constitute core elements for depressive relapses in the vulnerability model of mindfulness-based cognitive therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aims: β-Adrenoceptors (β-ADRs) mediating the relaxation of rat superior mesenteric arteries (SMAs) were pharmacologically identified, and the effects of chemical sympathetic denervation on β-ADR-mediated relaxation were examined., Main Methods: The tension changes of endothelium-denuded SMAs were isometrically recorded and the mRNA of endothelium-denuded SMA β-ADR was detected using RT-PCR., Key Findings: In endothelium-denuded SMAs contracted with ≥10 -7  M phenylephrine (an α 1 -ADR agonist), isoprenaline (a β-ADR agonist)-induced relaxation was competitively inhibited by 3 × 10 -9 -10 -8  M propranolol (a β 1,2 -ADR antagonist), but not further affected by ≥10 -8  M propranolol. Although isoprenaline-induced relaxation was not affected by ICI-118,551 (10 -9 -10 -8  M; a β 2 -ADR antagonist), it was competitively inhibited by atenolol (10 -7 -3 × 10 -7  M; a β 1 -ADR antagonist) in the presence of ICI-118,551. In the presence of 10 -7  M propranolol, isoprenaline- and CGP-12177A (a β 3 -ADR partial agonist)-induced relaxation was competitively inhibited by high concentrations of bupranolol (a β 1,2,3 -ADR antagonist), with pA 2 values of 6.49 and 5.76, respectively. We detected the mRNA of β 1 - and β 3 -ADRs in endothelium-denuded SMAs. Treatment with 6-hydroxydopamine (a catecholaminergic neurotoxin) reduced maximal isoprenaline-induced relaxation in the presence and absence of 10 -7  M propranolol, but not CGP-12177A-induced relaxation., Significance: Isoprenaline-induced relaxation of rat SMAs is mediated by β 1 - and β 3 -ADRs. β-ADR-mediated relaxation of rat SMAs is shown to be attenuated by chemical sympathetic denervation. The differences in the effects of bupranolol and chemical sympathetic denervation on the responses to isoprenaline and CGP-12177A in rat SMAs might be explained by the possible presence of multiple β 3 -ADRs with different pharmacological properties., (Copyright © 2019. Published by Elsevier Inc.)

Objective: Clinical assessment of upper extremity in multiple sclerosis is mainly limited to 9-hole peg test (9-HPT), which is commonly criticized due to its limited sensitivity. There is a need for sensitive outcome measures for the assessment of motor symptoms in individuals with multiple sclerosis (iMS). We evaluated our recently developed brief force pulse protocol to simultaneously quantify the motor control of hand function and neuromuscular quickness in iMS. Additionally, we compared the sensitivity of the studied outcome measures with 9-HPT in detecting the differences between iMS and controls., Methods: Twelve iMS and 12 controls grasped a grip- (GF; perpendicular force) and load-force (LF; tangential force) measuring handle and produced around 100 isometric LF pulses to various submaximal levels by pushing down on it as quickly as possible, followed by quick relaxation. The GF-LF ratio quantified the motor control of hand function. The slopes of linear regressions between peak forces and corresponding peak rates of force development (rate of force development scaling factor; RFD-SF) and relaxation (rate of force relaxation scaling factor; RFR-SF) quantified the control of neuromuscular quickness., Results: All of the selected variables were different between groups (all p-values < .05), and the effect sizes obtained from RFD-SF (d = 2.87) and RFR-SF (d = 1.93) were larger than the effect sizes obtained from 9-HPT (d = 1.07)., Conclusion: Measures of neuromuscular quickness are more sensitive to detect disease related differences than 9-HPT and, therefore, can be used as a tool in clinical and rehabilitative settings to objectively evaluate therapeutic interventions and disease progression in iMS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Computerized interpretation bias modification (IBM) programs show promise for the treatment of anxiety disorders, though they have rarely been compared to active treatments. The goal of the present study was to compare the efficacy of IBM to progressive muscle relaxation (PMR) for the treatment of social anxiety disorder (SAD). Sixty-four participants with SAD were recruited from across the United States and randomly assigned to 8 internet-delivered twice-weekly sessions of IBM or PMR. Participants were administered assessments of primary symptom outcomes and interpersonal suicide risk factors at posttreatment and 3-month follow-up. IBM led to significantly lower negative interpretation bias than PMR at posttreatment but not follow-up. Both conditions experienced comparable reductions in social anxiety from pretreatment to follow-up (IBM d = 1.37, PMR d = 1.28). They also experienced significant reductions in depression and general anxiety that did not differ from one another. Additionally, IBM led to greater reductions in thwarted belongingness than PMR at posttreatment but not follow-up. Overall, these findings suggest IBM is not more effective than PMR for reducing social anxiety, though there was some evidence of its superiority in decreasing suicide risk. Limitations and directions for future research are discussed., (Copyright © 2019. Published by Elsevier Ltd.)

Background/aims: Transient lower esophageal sphincter relaxations (TLESRs) are the major cause of gastroesophageal reflux. Recently, an EP1 receptor antagonist, ONO-8539, showed the reduction of TLESRs in monkeys. However, its effect on TLESRs in humans remains unclear. This study investigated the effect of ONO-8539 on postprandial TLESRs in healthy male subjects., Methods: Twenty-seven subjects participated in this placebo-controlled, cross-over study. The subjects received either placebo or ONO-8539 (450 mg) after a standardized breakfast. A 30-min basal recording was performed 4 h after drug administration. Subsequently, TLESR recordings were performed after a high-fat test meal for 3 h. The examination was repeated at least 7 days from the first evaluation for washout., Results: Thirteen patients were ultimately analyzed. The basal lower esophageal sphincter pressure was not different between the 2 groups (16.3 and 18.0 mm Hg for placebo and ONO-8539, respectively; p = 0.88). ONO-8539 significantly reduced the number of TLESRs from 15.0 to 12.0 for 3 h (p < 0.05). The proportion of terminating events of TLESRs was significantly different between the 2 groups (p < 0.05). No events and swallowing terminated more TLESRs with ONO-8539 than with placebo., Conclusions: ONO-8539 suppressed TLESRs mildly. EP1 receptor may be involved with the mechanism of human TLESRs., (© 2019 S. Karger AG, Basel.)

Increased lower esophageal sphincter integrated relaxation pressure (LES-IRP) is a cardinal feature of achalasia. However, some patients with characteristic features of achalasia have normal LES-IRP. 1,2 The efficacy of peroral endoscopic myotomy (POEM) in achalasia patients with normal LES-IRP is not well known. Hence, we aimed to compare POEM outcomes in achalasia patients with normal (<15 mm Hg) and increased (≥15 mm Hg) LES-IRP., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Using a relaxant agent before an endoscopic retrograde cholangiopancreatography (ERCP) might reduce complications., Study Aims: We aimed to investigate the relaxant effects of proton pump inhibitors (PPIs) on sheep sphincter of Oddi (SO) and the mechanisms that might take part in this relaxant effect., Patients and Methods: The sheep SO was mounted in an organ bath filled with Krebs-Ringer bicarbonate solution under 1.5 g tension and the relaxant effects of PPIs were evaluated in the tissues precontracted by carbachol (10 -6 mol/l). The relaxant responses to the PPIs were tested in the presence of various blockers to enlighten the underlying mechanism by the PPIs., Results: The PPIs exerted relaxant responses in a concentration-dependent manner in the sheep SO (P < 0.05). Esomeprazole produced the strongest relaxation. The administration of atropine, indomethacin, L-NAME, methylene blue, clotrimazole, glibenclamide, and 4-aminopyridine into the organ baths did not change the relaxations induced by PPIs in vitro (P> 0.05). On the other hand, Ca +2 -activated potassium channel blocker tetraethylammonium (TEA) reduced the relaxation responses created by PPIs (P < 0.05)., Conclusions: The present study suggests that PPIs create relaxation on SO partially via Ca +2 -activated potassium channels. PPIs, especially esomeprazole, may be beneficial during the ERCP procedure. Further clinical studies are needed to confirm our results., Competing Interests: None

Recent research using high-density electromyography (HDEMG) has provided a more precise understanding of the behaviour of the paraspinal muscles in people with low back pain (LBP); but so far, HDEMG has not been used to investigate the flexion relaxation phenomenon (FRP). To evaluate this, HDEMG signals were detected with grids of electrodes (13 × 5) placed bilaterally over the lumbar paraspinal muscles in individuals with and without LBP as they performed repetitions of full trunk flexion. The root mean square of the HDEMG signals was computed to generate the average normalized amplitude; and the spatial FRP onset was determined and expressed as percentage of trunk flexion. Smoothing spline analysis of variance models and the contrast cycle difference approach using the Bayesian interpretation were used to determine statistical inference. All pain-free controls and 64.3% of the individuals with LBP exhibited the FRP. Individuals with LBP and the FRP exhibited a delay of its onset compared to pain-free controls (significant mean difference of 13.3% of trunk flexion).  They also showed reduced normalized amplitude compared to those without the FRP, but still greater than pain-free controls (significant mean difference of 27.4% and 11.6% respectively). This study provides novel insights into changes in lumbar muscle behavior in individuals with LBP.

Background: The gastric accommodation reflex consists of a relaxation which creates a reservoir for the ingested food before emptying to the duodenum occurs. The mechanisms that control gastric accommodation are not fully understood. This study aims to use intragastric pressure (IGP) measurement and pyloric balloon obstruction to determine the contribution of duodenal nutrient exposure to gastric accommodation and meal-induced satiation., Methods: Two conditions were tested in 11 healthy subjects (28.3 ± 3.2 years; 23.6 ± 0.7 kg/m 2 ; four females). IGP was measured during an intragastric nutrient drink (ND) infusion at a constant rate (60 mL/min) in the presence of a deflated (control) or inflated (pyloric obstruction) balloon placed into the pylorus. During the study, subjects filled out Likert scales for satiation scores and visual analogue scale for 9 epigastric symptoms (hunger, expected amount to eat, satiation, bloating, fullness, nausea, belching, gastric cramps, and pain) before and during ND infusion until maximal satiation., Key Results: During pyloric obstruction, the IGP drop and the area above the IGP curve (AAC) were significantly smaller compared with the control condition (6.7 ± 1.0 mm Hg vs3.6 ± 0.8 mm Hg, P = .03 and 69.7 ± 13.5 mm Hg × min vs 20.1 ± 9.0 mm Hg × min, P = .001, respectively). Pyloric obstruction decreased nutrient tolerance compared with the control condition (787.9 ± 73.1 mL vs 970.9 ± 79.2 mL, respectively, P < .05). Pyloric obstruction increased symptoms of bloating (1.3 ± 0.4 vs 2.6 ± 0.6; P = .04), fullness (2.3 ± 0.5 vs 3.6 ± 0.3; P = .03), and nausea (0.4 ± 0.2 vs 1.3 ± 0.4; P = .04) compared to control., Conclusion & Inferences: Duodenal nutrient exposure contributes to enhancing gastric accommodation. Preventing the passage of nutrients from the stomach to the duodenum inhibits gastric accommodation and increases meal-induced satiation, bloating, nausea, and fullness., (© 2019 John Wiley & Sons Ltd.)

Aim: To examine the effects of progressive muscle relaxation combined with music on stress, fatigue and coping styles amongst intensive care unit (ICU) nurses., Design: A randomised controlled trial of 56 nurses aged 18  years and older, with at least three months experience. The intervention group (n = 28) received a 20 minute session comprising progressive muscle relaxation combined with music for a total of eight weeks in the form of group sessions, while the control group (n = 28) received only a single-time face-to-face attention-matched education (20  minutes). The data collection tools were administered at baseline, at week four, eight and twelve., Setting: Internal Medicine, Anaesthesia, and Coronary Intensive care Unit of a training and research hospital., Main Outcome Measures: Primary outcome: Stress level. Secondary outcome: Fatigue severity and coping styles., Results: Stress scores in the intervention group decreased significantly at week 8 and week 12 (p < 0.05). Similarly, the fatigue scores were observed to be significantly lower in the intervention group at week 8 and week 12 in comparison to those in the control group (p < 0.05). The scores of coping styles, obtained for the acceptance sub-dimension were significantly higher in the intervention group compared to the control group at week 4, 8, and 12 (p < 0.05). The use of instrumental support, venting and the emotional support scores were observed to be significantly higher in the intervention group compared to the control group at week 12 (p < 0.05)., Conclusion: The results indicated that progressive muscle relaxation combined with music appears to be effective in decreasing stress and fatigue, and in improving the coping styles amongst intensive care nurses. Future studies should be conducted on a larger scale to make conclusions with higher probability., (Copyright © 2019 Elsevier Ltd. All rights reserved.)