Disorders of gallbladder motility can lead to serious pathology. Bitter tastants acting upon bitter taste receptors (TAS2R family) have been proposed as a novel class of smooth muscle relaxants to combat excessive contraction in the airways and other organs. To explore whether this might also emerge as an option for gallbladder diseases, we here tested bitter tastants for relaxant properties and profiled Tas2r expression in the mouse gallbladder. In organ bath experiments, the bitter tastants denatonium, quinine, dextromethorphan, and noscapine, dose-dependently relaxed the pre-contracted gallbladder. Utilizing gene-deficient mouse strains, neither transient receptor potential family member 5 (TRPM5), nor the Tas2r143/Tas2r135/Tas2r126 gene cluster, nor tuft cells proved to be required for this relaxation, indicating direct action upon smooth muscle cells (SMC). Accordingly, denatonium, quinine and dextromethorphan increased intracellular calcium concentration preferentially in isolated gallbladder SMC and, again, this effect was independent of TRPM5. RT-PCR revealed transcripts of Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, and analysis of gallbladders from mice lacking tuft cells revealed preferential expression of Tas2r108 and Tas2r137 in tuft cells. A TAS2R143-mCherry reporter mouse labeled tuft cells in the gallbladder epithelium. An in silico analysis of a scRNA sequencing data set revealed Tas2r expression in only few cells of different identity, and from in situ hybridization histochemistry, which did not label distinct cells. Our findings demonstrate profound tuft cell- and TRPM5-independent relaxing effects of bitter tastants on gallbladder smooth muscle, but do not support the concept that these effects are mediated by bitter receptors.

G-protein-coupled receptors (GPCRs) belonging to the type 2 taste receptors (TAS2Rs) family are predominantly present in taste cells to allow the perception of bitter-tasting compounds. TAS2Rs have also been shown to be expressed in human airway smooth muscle (ASM), and TAS2R agonists relax ASM cells and bronchodilate airways despite elevating intracellular calcium. This calcium \"paradox\" (calcium mediates contraction by pro-contractile Gq-coupled GPCRs) and the mechanisms by which TAS2R agonists relax ASM remain poorly understood. To gain insight into pro-relaxant mechanisms effected by TAS2Rs, we employed an unbiased phosphoproteomic approach involving dual-mass spectrometry to determine differences in the phosphorylation of contractile-related proteins in ASM following the stimulation of cells with TAS2R agonists, histamine (an agonist of the Gq-coupled H1 histamine receptor) or isoproterenol (an agonist of the Gs-coupled β2-adrenoceptor) alone or in combination. Our study identified differential phosphorylation of proteins regulating contraction, including A-kinase anchoring protein (AKAP)2, AKAP12, and RhoA guanine nucleotide exchange factor (ARHGEF)12. Subsequent signaling analyses revealed RhoA and the T853 residue on myosin light chain phosphatase (MYPT)1 as points of mechanistic divergence between TAS2R and Gs-coupled GPCR pathways. Unlike Gs-coupled receptor signaling, which inhibits histamine-induced myosin light chain (MLC)20 phosphorylation via protein kinase A (PKA)-dependent inhibition of intracellular calcium mobilization, HSP20 and ERK1/2 activity, TAS2Rs are shown to inhibit histamine-induced pMLC20 via inhibition of RhoA activity and MYPT1 phosphorylation at the T853 residue. These findings provide insight into the TAS2R signaling in ASM by defining a distinct signaling mechanism modulating inhibition of pMLC20 to relax contracted ASM.

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.
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.
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.
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.

Securing an airway enables the oxygenation and ventilation of the lungs and is a potentially life-saving medical procedure. Adverse and critical events are common during airway management, particularly in neonates and infants. The multifactorial reasons for this include patient-dependent, user-dependent and also external factors. The recently published joint ESAIC/BJA international guidelines on airway management in neonates and infants are summarized with a focus on the clinical application. The original publication of the guidelines focussed on naming formal recommendations based on systematically documented evidence, whereas this summary focusses particularly on the practicability of their implementation.
UNASSIGNED: Die Sicherung der Atemwege ermöglicht die Oxygenierung und Ventilation der Lungen und stellt eine potenziell lebensrettende medizinische Maßnahme dar. Insbesondere bei Neugeborenen und Säuglingen kommt es gehäuft zu unerwünschten und kritischen Ereignissen während des Atemwegsmanagements. Die multifaktoriellen Gründe dafür umfassen patientenabhängige, anwenderabhängige, aber auch externe Faktoren. Im Folgenden wird die neu erschienene internationale Leitlinie zur Atemwegssicherung bei Neugeborenen und Säuglingen fokussierend auf die klinische Anwendung zusammengefasst. Während die Originalpublikation der Leitlinie darauf fokussiert, auf Basis der systematisch erfassten Evidenz formale Empfehlungen zu benennen, stellt diese Zusammenfassung v. a. die Praktikabilität ihrer Umsetzung in den Fokus.

The purpose of this research was to ascertain how progressive muscle relaxation (PMR) technique affected hip fracture patients\' anxiety, sleep quality, and post-operative pain. This parallel randomized controlled trial was conducted on 100 patients with hip fracture hospitalized in one of the reference orthopedic hospitals in Tehran, Iran who were selected using convenience sampling and randomly were placed in two PMR group (n = 50) and control group (n = 50). Data were collected by Demographic information questionnaire, Visual analogue scale for pain rating, Pittsburgh Sleep Quality Index and State-Trait Anxiety Inventory. The PMR technique was the progressive muscle relaxation technique, which was started the night after the surgery for three nights before going to bed. Data were collected on two occasions, including before the PMR technique and the day after the last stage of the PMR technique. The data were analyzed by SPSS software using descriptive and inferential statistics. The results revealed significant within-group changes in both groups\' post-operative pain, sleep quality, and anxiety scores (P < 0.001). The progressive muscle relaxation group experienced decreased post-operative pain and anxiety scores and increased sleep quality scores (P < 0.001). The linear mixed model showed that the absolute changes in the follow-up post-operative pain, sleep quality, and anxiety scores were 1.19 and 7.94 units, significantly lower than the baseline, respectively. The results revealed significant within-group changes in both groups\' post-operative pain, sleep quality, and anxiety scores (P < 0.001). The progressive muscle relaxation group experienced decreased post-operative pain and anxiety scores and increased sleep quality scores (P < 0.001). The study\'s findings demonstrated the beneficial effects of progressive muscle relaxation on hip fracture patients\' outcomes, such as their level of anxiety, sleep quality, and post-operative pain. The study\'s findings can be applied by medical professionals to improve patient satisfaction and care quality.This clinical trial has been registered with the Iranian Registry of Clinical Trials under the code IRCT20231120060119N1, which was approved on 7/12/2023.

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.

Numerous studies suggest the involvement of adenosine-5\'-triphosphate (ATP) and similar nucleotides in the pathophysiology of asthma. Androgens, such as testosterone (TES), are proposed to alleviate asthma symptoms in young men. ATP and uridine-5\'-triphosphate (UTP) relax the airway smooth muscle (ASM) via purinergic P2Y2 and P2Y4 receptors and K+ channel opening. We previously demonstrated that TES increased the expression of voltage-dependent K+ (KV) channels in ASM. This study investigates how TES may potentiate ASM relaxation induced by ATP and UTP. Tracheal tissues treated with or without TES (control group) from young male guinea pigs were used. In organ baths, tracheas exposed to TES (40 nM for 48 h) showed enhanced ATP- and UTP-evoked relaxation. Tetraethylammonium, a K+ channel blocker, annulled this effect. Patch-clamp experiments in tracheal myocytes showed that TES also increased ATP- and UTP-induced K+ currents, and this effect was abolished with flutamide (an androgen receptor antagonist). KV channels were involved in this phenomenon, which was demonstrated by inhibition with 4-aminopyridine. RB2 (an antagonist of almost all P2Y receptors except for P2Y2), as well as N-ethylmaleimide and SQ 22,536 (inhibitors of G proteins and adenylyl cyclase, respectively), attenuated the enhancement of the K+ currents induced by TES. Immunofluorescence and immunohistochemistry studies revealed that TES did not modify the expression of P2Y4 receptors or COX-1 and COX-2, while we have demonstrated that this androgen augmented the expression of KV1.2 and KV1.5 channels in ASM. Thus, TES leads to the upregulation of P2Y4 signaling and KV channels in guinea pig ASM, enhancing ATP and UTP relaxation responses, which likely limits the severity of bronchospasm in young males.

Movement and muscle control are crucial for the survival of all free-living organisms. This study aimed to explore differential patterns of cortical and subcortical activation across different stages of muscle control using functional magnetic resonance imaging (fMRI). An event-related design was employed. In each trial, participants (n = 10) were instructed to gently press a button with their right index finger, hold it naturally for several seconds, and then relax the finger. Neural activation in these temporally separated stages was analyzed using a General Linear Model. Our findings revealed that a widely distributed cortical network, including the supplementary motor area and insula, was implicated not only in the pressing stage, but also in the relaxation stage, while only parts of the network were involved in the steady holding stage. Moreover, supporting the direct/indirect pathway model of the subcortical basal ganglia, their substructures played distinct roles in different stages of muscle control. The caudate nucleus exhibited greater involvement in muscle contraction, whereas the putamen demonstrated a stronger association with muscle relaxation; both structures were implicated in the pressing stage. Furthermore, the subthalamic nucleus was exclusively engaged during the muscle relaxation stage. We conclude that even the control of simple muscle movements involves intricate automatic higher sensory-motor integration at a neural level, particularly when coordinating relative muscle movements, including both muscle contraction and muscle relaxation; the cortical and subcortical regions assume distinct yet coordinated roles across different stages of muscle control.

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 (KATP channels), glibenclamide (200 μM), inhibited the ATP-induced relaxation and application of an opener of KATP 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 KATP channels.

BACKGROUND: Fibromyalgia (FM) is characterized by idiopathic persistent chronic pain in the ligaments or musculoskeletal system, and more than half of the patients with FM might have migraine headaches. Direct musculoskeletal intervention could be a non-pharmacological management to relieve symptoms. However, patients with severe FM often have intense pain from only a soft touch, thereby rendering musculoskeletal intervention challenging.
METHODS: A 47-year-old man had progressing intense pain, and this affected his everyday life. There were no abnormal physical findings on laboratory examination such as levels of complement, antinuclear antibodies, and C-reactive protein, which were within normal limits. Magnetic resonance imaging did not indicate abnormalities.
METHODS: The patient satisfied the American College of Rheumatology criteria. Finally, we made a final diagnosis of fibromyalgia. The therapeutic intervention of Kanshoho, the unique muscle relaxation technique with low force, relieved his pain.
CONCLUSIONS: If Kanshoho is carefully applied in a state of hospitalization under surveillance by an experienced physician, it could be a promising muscle relaxation method. Relaxing the trapezius muscle and reducing its intramuscular pressure might be key in treating patients with severe FM. However, it needs elucidation of its mechanism.