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BACKGROUND: Cyclergometry with functional electrical stimulation (FES-cycling) is a feasible method for rehabilitation. The concept is to promote exercise induced by depolarization of the motoneuron and muscular contraction. OBJECTIVE: To measure acute physiological responses to FES-cycling. METHODS: Retrospective study of data from ten healthy volunteers who performed FES-cycling, passive cycling and neuromuscular electrical stimulation (NMES) alone. Metabolic, ventilatory and cardiovascular parameters were analyzed. RESULTS: Oxygen uptake enhanced 97 ± 15% during FES-cycling, with medium effect size compared to NMES and large effect size compared to passive cycling. Energy expenditure enhanced 102 ± 15% during FES-cycling, with medium effect size compared to NMES and large effect size compared to passive cycling. Minute ventilation enhanced 115 ± 26% during FES-cycling, with small effect size compared to NMES and medium effect size compared to passive cycling. Cardiac output enhanced 21 ± 4% during FES-cycling, with medium effect size compared to NMES and passive cycling. Arterial – mixed venous oxygen content difference enhanced 60 ± 8% during FES-cycling, with a medium effect size compared to NMES and large effect size compared to passive cycling. CONCLUSIONS: FES-cycling enhances metabolic, ventilatory and cardiovascular demands and the physiological responses are higher than NMES and passive cycling.

Scar contraction frequently happens in patients with deep burn injuries. Hitherto, porcine dermal extracellular matrix (dECM) has supplied microenvironments that assist in wound healing but fail to inhibit scar contraction. To overcome this drawback, we integrate dECM into three-dimensional (3D)-printed dermal analogues (PDA) to prevent scar contraction. We have developed thermally gelled, non-rheologically modified dECM powder (dECMp) inks and successfully transformed them into PDA that was endowed with a micron-scale spatial structure. The optimal crosslinked PDA exhibited desired structure, good mechanical properties as well as excellent biocompatibility. Moreover, in vivo experiments demonstrated that PDA could significantly reduced scar contraction and improved cosmetic upshots of split thickness skin grafts (STSG) than the commercially available dermal templates and STSG along. The PDA has also induced an early, intense neovascularization, and evoked a type-2-like immune response. PDA's superior beneficial effects may attribute to their desired porous structure, the well-balanced physicochemical properties, and the preserved dermis-specific ECM cues, which collectively modulated the expression of genes such as Wnt11, ATF3, and IL1β, and influenced the crucial endogenous signalling pathways. The findings of this study suggest that PDA is a clinical translatable material that possess high potential in reducing scar contraction., Graphical abstract Schematic of 3D-Printed dermis-specific extracellular matrix mitigates scar contraction.Image 1, Highlights • Current dermal analogues have supplied microenvironments that assist in wound healing but cannot inhibit scar contraction. • dECMp ink was formulated and transformed into PDA endowed with a micron-scale designed spatial structure. • The PDAs were neatly superior to split thickness skin grafts and commercial dermal templates in hindering scar contraction. • The transcriptome data may reveal how at the molecular level the IS and skin wounds respond to biomaterial stimuli.

Background/purpose As an extraction wound closes, the mucosal epithelium of the tooth extraction wound impedes the space for new bone formation by invading into the extraction socket. Thus, the height of the alveolar crest decreases, causing significant depression of the alveolar mucosa. In this study, we created a rat tooth extraction model and examined the effects of laser irradiation by CO2 and diode on the dynamics of myofibroblast expression through α-SMA, and TGF-β1. Materials and methods After tooth extraction of five-week-old male Wistar rats, they were divided into two laser treatment groups (CO2 laser or diode laser was irradiated into tooth extraction socket) and non-laser treatment group (control group). Surrounding tissues, including the extraction socket, were removed at 3, 5, 7, and 21 days after tooth extraction and the expression of α-SMA and TGF-β1 was verified using immunohistological techniques (6 animals in each group and each period, 72 animals in total). Results α-SMA-positive cells and TGF-β1-positive areas were significantly lower in the two laser treatment groups than in the control group. Particularly, the diode group almost had no TGF-β1-positive areas on the 21st day when healing after tooth extraction was deemed to be completed. Conclusion Both CO2 and diode laser irradiation of tooth extraction wounds decreases α-SMA-positive cells and TGF-β1-positive areas. Further, it causes a decrease in myofibroblast expression and suppresses the invasion of mucosal epithelium into the extraction socket. Therefore, laser irradiation may exert a space-making effect for new bone formation and also contribute to socket preservation.

Smooth muscle contraction is a basic homeostatic mechanism and, when dysfunctional, it is directly responsible for severe diseases like asthma and arterial hypertension. For decades, the standard technique to study contraction and evaluate the action of drugs has involved the use of isolated organ baths. However, the high cost of the dedicated personnel has led to their progressive replacement by techniques compatible with HTS. Nevertheless, preclinical evaluation of vasodilator or bronchodilator activity still requires direct evaluation of a drug’s effects. The multi-well organ bath (MuWOB) combines the possibility of using a robot to perform computer-controlled contraction and relaxation assays on arterial and tracheal tissue (rings) in largescale parallel analyses.

The pharyngeal airway behaves like an artificial collapsible tube within a rigid box. Any combinations of (1) increase of the tissue pressure surrounding the pharyngeal airway, (2) decrease of the intraluminal airway pressure, and (3) reduction of the longitudinal pharyngeal wall tension can collapse the pharyngeal airway and induce inspiratory flow limitation. Surface forces may contribute to the development of pharyngeal airway narrowing. Pharyngeal muscle contraction dilates and stiffens the pharyngeal airway by changing its mechanical properties. Wakefulness is the strongest stimulus to maintain the pharyngeal muscle activity.

Patients with chronic non-specific low back pain (CNSLBP) were found with impaired postural control in previous studies. Since the trunk muscle take important efforts on core stability, the study aimed to examine the relationships of postural control during stance tasks and the contractility of trunk muscle in young adults with CNSLBP and without.Healthy individuals (n = 25) and individuals with CNSLBP (n = 30) were included. The thickness of the bilateral transversus abdominis (TrA) and lumbar multifidus (MF) was measured during rest and maximal voluntary contraction, and the change percentages (TrA%, MF%) were calculated. Regarding postural control, COP path length and sway area during the stance tasks were measured thrice in each group.The bilateral TrA% of the CNSLBP group was less than that of the HC group (p 0.05). The bilateral TrA% of the CNSLBP group was less than that of the HC group (p 0.05). The bilateral MF% showed no significantly different(p 0.05) between the two groups. Compared with healthy controls, CNSLBP patients resulted larger path length and sway area of COP during most of static stance tasks. During the EO task in the CNSLBP group, TrA% was found correlate to COP path length (p 0.05); the right MF% was correlated with COP sway area (p 0.05). No significant correlations appeared in the healthy controls (p 0.05).Compared with healthy individuals, impaired postural control during static stance with eyes open in patients with CNSLBP was likely to be related to the poor contraction ability of bilateral transversus abdominis and correlated to the normal contraction ability of right lumbar multifidus.

Expiratory tasks may facilitate transversus abdominis (TrA) activity for spinal stabilization. The purpose of this study was to verify whether a combination of pursed-lip breathing (PLB) and use of an expiratory threshold loading (ETL) device to increase expiratory resistance would promote TrA contraction comparable to that for a stabilization exercise.Twenty healthy men performed expiratory tasks or an abdominal drawing-in maneuver (ADIM). Expiratory tasks comprised combinations of ETL settings with 0%, 5%, or 15% of maximum expiratory pressure, and mouthpieces with a normal shape or pursed-lip shape. B-mode ultrasound imaging of the TrA, internal oblique, and external oblique muscles was performed to determine percentage changes in muscle thickness. Percentage changes among tasks were statistically compared for each muscle.TrA thickness increased with normal lips at 15% ETL, with PLB with 5% ETL, and with ADIM (p 0.01 each). Internal oblique thickness increased under all PLB conditions (p 0.01 each). No significant differences in external oblique thickness were seen for any tasks. The total thickness of the lateral abdominal muscles was significantly increased not only for 15% ETL tasks and ADIM, but also for PLB with 5% ETL (p 0.02 each).These results indicated that PLB with 5% ETL could facilitate the same level of TrA activity as the ADIM. PLB with 5% ETL was the only task that simultaneously increased overall lateral abdominal muscles, including the internal obliques, and might be readily applicable in clinical situations.

Background Previous models describing the fetal-to-neonatal transition often lack oxygen saturation levels, homeostatic control mechanisms, phasic hemodynamic signals, or describe the heart with a time-varying elastance model. Methods We incorporated these elements in the adapted CircAdapt model with the one-fiber model for myocardial contraction, to simulate the hemodynamics of the healthy term human fetal circulation and its transition during the first 24 h after birth. The fetal-to-neonatal model was controlled by a time- and event-based script of changes occurring at birth, such as lung aeration and umbilical cord clamping. Model parameters were based on and validated with human and animal data. Results The fetal circulation showed low pulmonary blood flow, right ventricular dominance, and inverted mitral and tricuspid flow velocity patterns, as well as high mean ductus venosus flow velocity. The neonatal circulation showed oxygen saturation levels to gradually increase to 98% in the first 15 min after birth as well as temporary left ventricular volume overload. Conclusions Hemodynamics of the term fetus and 24-h-old neonate, as well as the events occurring directly after birth and the transition during the first 24 h after birth, were realistically represented, allowing the model to be used for educational purposes and future research. ImpactWith the addition of oxygen saturation levels, homeostatic pressure-flow control mechanisms, and the one-fiber model for myocardial contraction, a new closed-loop cardiovascular model was constructed to give more insight into the healthy term human fetal circulation and its cardiovascular transition during the first 24 h after birth. Extensive validation confirmed that the hemodynamics of the term fetus and the fetal-to-neonatal transition were realistically represented with the model. This well-validated and versatile model can serve as an education as well as a research platform for in silico investigation of fetal-to-neonatal hemodynamic changes under a wide range of physiological and pathophysiological conditions.

Although maximal force increases following short-term isometric strength training, the rate of force development (RFD) may remain relatively unaffected. The underlying neural and muscular mechanisms during rapid contractions after strength training are largely unknown. Since strength training increases the neural drive to muscles, it may be hypothesized that there are distinct neural or muscular adaptations determining the change in RFD independently of an increase in maximal force. Therefore, we examined motor unit population data acquired from surface electromyography during the rapid generation of force before and after 4 wk of strength training. We observed that strength training did not change the RFD because it did not influence the number of motor units recruited per second or their initial discharge rate during rapid contractions. Although strength training did not change motoneuron behavior in the force increase phase of rapid contractions, it increased the discharge rate of motoneurons (by ∼4 spikes/s) when reaching the plateau phase (∼150 ms) of the rapid contractions, determining an increase in maximal force production. Computer simulations with a motor unit model that included neural and muscular properties, closely matched the experimental observations and demonstrated that the lack of change in RFD following training is primarily mediated by an unchanged maximal recruitment speed of motoneurons. These results demonstrate that maximal force and contraction speed are determined by different adaptations in motoneuron behavior following strength training and indicate that increases in the recruitment speed of motoneurons are required to evoke training-induced increases in RFD.NEW & NOTEWORTHY Although maximal force increases with strength training, the rate of force development may remain unaffected. For the first time, we associated motor unit population behavior during rapid force contractions before and after a 4-wk isometric strength training intervention. We found that strength training combined with slow and rapid contractions does not change rate of force development. The specific mechanisms include similar discharge rate during the initial phase of contraction and similar recruitment speed of motoneurons.

The pro-inflammatory cytokine tumor necrosis factor (TNF)-α augments intracellular Ca2+ signaling and contractile responses of airway smooth muscles, leading to airway hyperresponsiveness (AHR). However, the underlying mechanism has not been fully elucidated. This study aims to investigate the cellular mechanism of the potentiated contraction of mouse tracheal smooth muscle induced by TNF-α. The results revealed that TNF-α triggered facilitation of mouse tracheal smooth muscle contraction in an epithelium-independent manner. The TNF-α-induced hypercontractility could be suppressed by the protein kinase C (PKC) inhibitor GF109203X, the tyrosine kinase inhibitor genistein, the Src inhibitor PP2 or the L-type voltage-dependent Ca2+ channel blocker nifedipine. After TNF-α incubation, the α1C L-type Ca2+ channel (CaV1.2) was up-regulated in primary cultured mouse tracheal smooth muscle cells. Pronounced phosphotyrosine level was also observed in mouse tracheas. In conclusion, this study demonstrated that TNF-α enhanced airway smooth muscle contraction via PKC- Src-CaV1.2 pathways, which provides novel insights into the pathological role of pro-inflammatory cytokines in mediating AHR.

Objective We reviewed and appraised the existing evidence of in vivo manifestations of residual force enhancement in human skeletal muscles and assessed, through a meta-analysis, the effect of an immediate history of eccentric contraction on the subsequent torque capacity of voluntary and electrically evoked muscle contractions. Methods Our search was conducted from database inception to May 2020. Descriptive information was extracted from, and quality was assessed for, 45 studies. Meta-analyses and metaregressions were used to analyze residual torque enhancement and its dependence on the angular amplitude of the preceding eccentric contraction. Results Procedures varied across studies with regards to muscle group tested, angular stretch amplitude, randomization of contractions, time window analyzed, and verbal command. Torque capacity in isometric (constant muscle tendon unit length and joint angle) contractions preceded by an eccentric contraction was typically greater compared to purely isometric contractions, and this effect was greater for electrically evoked muscle contractions than voluntary contractions. Residual torque enhancement differed across muscle groups for the voluntary contractions, with a significant enhancement in torque observed for the adductor pollicis, ankle dorsiflexors, ankle plantar flexors, and knee extensors, but not for the elbow and knee flexors. Meta-regressions revealed that the angular amplitude of the eccentric contraction (normalized to the respective joint's full range of motion) was not associated with the residual torque enhancement observed. Conclusion There is evidence of residual torque enhancement for most, but not all, muscle groups, and residual torque enhancement is greater for electrically evoked than for voluntary contractions. Contrary to our hypothesis, and contrary to generally accepted findings on isolated muscle preparations, residual torque enhancement in voluntary and electrically evoked contractions does not seem to depend on the angular amplitude of the preceding eccentric contraction.

Refereed/Peer-reviewed Age-related changes in the neuromuscular system can result in differences in fatigability between young and older adults. Previous research has shown that single-joint isometric fatiguing exercise of small muscle results in an age-related compensatory decrease in c-aminobutyric acid (GABAB)-mediated inhibition. However, this has yet to be established in a larger muscle group. In 15 young (22 ± 4 yr) and 15 older (65 ± 5 yr) adults, long interval cortical inhibition [LICI; 100 ms Interstimulus interval (ISI)] and corticospinal silent period (SP) were measured in the biceps brachii during a 5% electromyography (EMG) contraction using transcranial magnetic stimulation (TMS) before, during, and after a submaximal contraction [30% of maximum voluntary contraction (MVC) force] held intermittently to task failure. Both age groups developed similar magnitude of fatigue (∼24% decline in MVC; P = 0.001) and ∼28% decline in LICI (P = 0.001) post fatiguing exercise. No change in SP duration was observed during and immediately following fatigue (P = 0.909), but ∼6% decrease was seen at recovery in both age groups (P < 0.001). Contrary to previous work in a small muscle, these findings suggest no age-related differences in GABAB-mediated inhibition following single-joint isometric fatiguing exercise of the elbow flexors, indicating that GABAB modulation with aging may be muscle group dependent. Furthermore, variations in SP duration and LICI modulation during and post fatigue in both groups suggest that these measures are likely mediated by divergent mechanisms. New & Noteworthy: Transcranial magnetic stimulation was used to examine GABAB-mediated inhibition during fatiguing exercise of large muscle group in older adults and young adults. We provide novel evidence to show that when older and young adults are faced with a similar magnitude of elbow flexor muscle fatigue, they have a similar decline in GABAB-mediated inhibition. This suggests that when measured in a large muscle group, older adults maintain the ability to modulate GABAB inhibition during fatiguing exercise.

PURPOSE Left atrial (LA) phasic functions in various subgroups of subjects with obesity are differently impaired, suggesting that obesity may have diverse effects in dissimilar subgroups of subjects with obesity. We aimed to compare the effects of obesity on LA phasic functions in patients suffering from chronic ischemic heart disease with a preserved left ventricular ejection fraction and without a recent myocardial infarction. METHODS In our cross-sectional study, 145 consecutive candidates for isolated coronary artery bypass graft (CABG) surgery were divided according to the presence of obesity into 2 groups: obese (36 patients) and nonobese (103 patients), and LA phasic functions were evaluated by two-dimensional speckle-tracking echocardiography (2D STE). RESULTS The longitudinal strain rate during the reservoir phase (3.0 ± 0.7 s-1 vs 2.7 ± 0.6 s-1; P = 0.032), longitudinal strain during the contraction phase (19.2 ± 4.7% vs 17.2 ± 4.1%; P = 0.022), and the longitudinal strain rate during the contraction phase (4.4 ± 1.2 s-1 vs 3.9 ± 1.2 s-1; P = 0.036) decreased in the obese group compared with the nonobese group. The other longitudinal 2D STE-derived markers of the LA phasic functions were not different between the 2 groups. CONCLUSIONS Among patients suffering from chronic ischemic heart disease with a preserved left ventricular ejection fraction and without a recent myocardial infarction, LA reservoir and contraction functions as measured by 2D STE were impaired in patients with obesity compared with those without it.

Chronic rotator cuff tears can cause severe functional deficits. Addressing the chronic fatty and fibrotic muscle changes is of high clinical interest; however, the architectural and physiological consequences of chronic tear and repair are poorly characterized. We present a detailed architectural and physiological analysis of chronic tear and repair (both over 8 and 16 wk) compared with age-matched control rabbit supraspinatus (SSP) muscles. Using female New Zealand White Rabbits (n = 30, n = 6/group) under 2% isoflurane anesthesia, the SSP was surgically isolated and maximum isometric force was measured at four to six muscle lengths. Architectural analysis was performed, and maximum isometric stress was computed. Whole muscle length-tension curves were generated using architectural measurements to compare experimental physiology to theoretical predictions. Architectural measures are consistent with persistent radial and longitudinal atrophy over time in tenotomy that fails to recover after repair. Maximum isometric force was significantly decreased after 16 wk tenotomy and not significantly improved after repair. Peak isometric force reported here are greater than prior reports of rabbit SSP force after tenotomy. Peak stress was not significantly different between groups and consistent with prior literature of SSP stress. Muscle strain during contraction was significantly decreased after 8 wk of tenotomy and repair, indicating effects of tear and repair on muscle function. The experimental length-tension data were overlaid with predicted curves for each experimental group (generated from structural data), exposing the altered structure-function relationship for tenotomy and repair over time. Data presented here contribute to understanding the physiological implications of disease and repair in the rotator cuff. NEW & NOTEWORTHY We utilize an established method to measure the length-tension relationship for the rabbit supraspinatus in normal, torn, and repaired muscles. We then perform architectural analysis to evaluate structural changes after tear and repair. Although peak isometric force is lower in the tear and repair groups, there are no differences in peak stresses across groups. These findings indicate persistent structural changes (both radial and longitudinal atrophy) and physiological deficiencies (decreased peak force and uncoupling structure-function relationship) after tenotomy that do not significantly recover after repair.

The aim of this study was to determine if stimulation of sacral spinal nerve roots can induce defecation in cats. In anesthetized cats, bipolar hook electrodes were placed on the S1-S3 dorsal and/or ventral roots. Stimulus pulses (1-50 Hz, 0.2 ms) were applied to an individual S1-S3 root to induce proximal/distal colon contractions and defecation. Balloon catheters were inserted into the proximal and distal colon to measure contraction pressure. Glass marbles were inserted into the rectum to demonstrate defecation by videotaping the elimination of marbles. Stimulation of the S2 ventral root at 7 Hz induced significantly (p

Compromised endothelial (EC) barrier function is a hallmark of inflammatory diseases. Mammalian target of rapamycin (mTOR) inhibitors, widely applied as clinical therapies, cause pneumonitis throug...

Nocturnal asthma is characterized by heightened bronchial reactivity at night, and plasma melatonin concentrations are higher in patients with nocturnal asthma symptoms. Numerous physiological effects of melatonin are mediated via its specific G protein-coupled receptors (GPCRs) named the MT1 receptor, which couples to both Gq and Gi proteins, and the MT2 receptor, which couples to Gi. We investigated whether melatonin receptors are expressed on airway smooth muscle; whether they regulate intracellular cyclic AMP (cAMP) and calcium concentrations ([Ca2+]i), which modulate airway smooth muscle tone; and whether they promote airway smooth muscle cell proliferation. We detected the mRNA and protein expression of the melatonin MT2 but not the MT1 receptor in native human and guinea pig airway smooth muscle and cultured human airway smooth muscle (HASM) cells by RT-PCR, immunoblotting, and immunohistochemistry. Activation of melatonin MT2 receptors with either pharmacological concentrations of melatonin (10–100 µM) or the nonselective MT1/MT2 agonist ramelteon (10 µM) significantly inhibited forskolin-stimulated cAMP accumulation in HASM cells, which was reversed by the Gαi protein inhibitor pertussis toxin or knockdown of the MT2 receptor by its specific siRNA. Although melatonin by itself did not induce an initial [Ca2+]i increase and airway contraction, melatonin significantly potentiated acetylcholine-stimulated [Ca2+]i increases, stress fiber formation through the MT2 receptor in HASM cells, and attenuated the relaxant effect of isoproterenol in guinea pig trachea. These findings suggest that the melatonin MT2 receptor is expressed in ASM, and modulates airway smooth muscle tone via reduced cAMP production and increased [Ca2+]i.

The myocardial contraction fraction (MCF) is proposed as an improved measure of left ventricular (LV) systolic function that overcomes important limitations of the left ventricular ejection fraction (LVEF). We sought to determine whether a low MCF was associated with higher mortality in cardiac intensive care unit (CICU) patients.We retrospectively analyzed unique Mayo Clinic CICU patients from 2007 to 2018 with MCF calculated as the ratio of the stroke volume to the left ventricular myocardial volume from a transthoracic echocardiogram within 1 day of CICU admission. Multivariable logistic regression analyzed the association between MCF and hospital mortality, after adjustment for LVEF and clinical variables.We included 4794 patients with a mean age of 68.0 ± 14.8 years (37.1% females). The mean MCF was 0.41 ± 0.16, and was lower in the 6.6% of patients who died in the hospital (0.32 ± 0.14 versus 0.42 ± 0.16, p 0.001). On multivariable analysis, higher MCF remained associated with lower hospital mortality (adjusted OR 0.78 per 0.1 higher, 95% CI 0.69-0.89, p 0.001), whereas LVEF was not significantly associated with hospital mortality (unadjusted OR 0.91 per 10% higher, OR 95% CI 0.82-1.02, p = 0.09). Patients with MCF0.2 had the highest in-hospital mortality, and those with MCF ≥0.5 had the lowest in-hospital mortality, irrespective of admission diagnosis or LVEF.MCF demonstrated a strong, inverse relationship with hospital mortality in CICU patients, even after adjusting for LVEF and clinical variables. MCF can be used to identify prognostically-relevant myocardial dysfunction at the bedside, even among patients with preserved LVEF.

INTRODUCTION AND HYPOTHESIS There is a lack of in-depth understanding of the muscles surrounding the pelvic floor muscle (PFM). The study aimed to investigate the functional relationship between PFM and hip external rotator muscles by observing the piriformis muscle thickness and displacement of the bladder base under different contraction conditions of the hip external rotator and/or PFM. We hypothesized that PFM function would be the strongest when the hip external rotator and PFM contracted simultaneously and that during PFM contraction, the piriformis muscle would act as an auxiliary muscle and show coactivation. METHODS The participants included 13 healthy adult women (mean age 23.8 ± 2.8 years). The three contraction conditions were PFM contraction, hip external rotator contraction, and simultaneous contraction of the hip external rotator and PFM. During the tasks, the piriformis muscle thickness and bladder base displacement were measured using ultrasonography and compared among the contraction conditions using one-way analysis of variance. RESULTS Significant differences were noted in bladder base displacement among the three contraction conditions (P

Anacardium occidentale (Ao) is widely used in ethnomedicine and the effect on contractility of the gut and heart muscles of laboratory rodents have been established however, its effect on the contractility of uterine muscle has been rarely researched. The present study investigated the effect of stem bark methanolic extract of Anacardium occidentale (AoME) on Isolated Rat Uterus Strips (IRUS). The Anacardium occidentale methanol extract (AoME) was obtained by solvent extraction. The IRUS were suspended in a bath containing 15 ml of De Jalon's solution through a silk connected to a force transducer. A tension of 1.0 g was applied. The strips were allowed to equilibrate for a period of 60–90 min before the commencement of the experiment. The extract (0.025- 0.3mg/ml) added cumulatively did not modify the normal tonus in most of the IRUS used except in one where it feebly contracted it. However, the contractile responses induced by acetylcholine (10-9 -10-5 M) and oxytocin (10-9 -10-5 M) on the IRUS were almost completely blocked by pre-incubated AoME at a concentration of 0.2 mg/ml. Stem bark methanol extract of Anacardium occidentale shifted the log concentration curve of both agonists to the right. The present results report the antagonistic effects of stem bark methanol extract of Anacardium occidentale on oxytocin and acetylcholine-induced contraction in rat uterus strips. Keywords: Anacardium occidentale, Oxytocin, Acetylcholine, Uterus, Smooth muscle

Naturally found chrysosplenol-C (49,5,6-trihydroxy-3,39,7-trimethoxyflavone) increases the contractility of cardiac myocytes independent of b-adrenergic signaling. We investigated the cellular mechanism for chrysosplenol-C-induced positive inotropy. Global and local Ca2+ signals, L-type Ca2+ current (ICa), and contraction were measured from adult rat ventricular myocytes using two-dimensional confocal Ca2+ imaging, the whole-cell patch clamp technique, and video-edge detection, respectively. Application of chrysosplenol-C reversibly increased Ca2+ transient magnitude with a maximal increase of ~55% within 2-3-min-exposures (EC50 =~21 mM). This chemical did not alter ICa and slightly increased diastolic Ca2+ level. The frequency and size of resting Ca2+ sparks were increased by chrysosplenol-C. Chrysosplenol-C significantly increased sarcoplasmic reticulum (SR) Ca2+ content but not fractional release. Pretreatment of protein kinase C (PKC) inhibitor, but not Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor, abolished the stimulatory effects of chrysosplenol-C on Ca2+ transients and Ca2+ sparks. Chrysosplenol-C-induced positive inotropy was removed by the inhibition of PKC, but not CaMKII or phospholipase C. Western blotting assessment revealed that PKC-δ protein level in the membrane fractions significantly increase within 2 min after chrysosplenol-C exposure with a delayed (5 min) increase in PKC-α levels in insoluble membrane. These results suggest that chrysosplenol-C enhances contractility via PKC (most likely PKC-δ)-dependent enhancement of SR Ca2+ releases in ventricular myocytes. Significance Statement We show that chrysosplenol-C, a natural flavone showing a positive inotropic effect, increases sarcoplasmic reticulum (SR) Ca2+ releases on depolarizations and Ca2+ sparks with an increase of SR Ca2+ loading, but not L-type Ca2+ current, in ventricular myocytes. Chrysosplenol-C-induced enhancement in contraction is eliminated by protein kinase C (PKC) inhibition, and it is associated with redistributions of PKC to the membrane. These indicate that chrysosplenol-C enhances contraction via PKC-dependent augmentations of SR Ca2+ release and Ca2+ loading during action potentials.

The common null polymorphism (R577X) in the ACTN3 gene is present in over 1.5 billion people worldwide and results in the absence of the protein α-actinin-3 from the Z-discs of fast-twitch skeletal muscle fibres. We have previously reported that this polymorphism is a modifier of dystrophin deficient Duchenne Muscular Dystrophy. To investigate the mechanism underlying this we use a double knockout (dk)Actn3KO/mdx (dKO) mouse model which lacks both dystrophin and sarcomere α-actinin-3. We used dKO mice and mdx dystrophic mice at 12 months (aged) to investigate the correlation between morphological changes to the fast-twitch dKO EDL and the reduction in force deficit produced by an in vitro eccentric contraction protocol. In the aged dKO mouse we found a marked reduction in fibre branching complexity that correlated with protection from eccentric contraction induced force deficit. Complex branches in the aged dKO EDL fibres (28%) were substantially reduced compared to aged mdx EDL fibres (68%) and this correlates with a graded force loss over three eccentric contractions for dKO muscles (∼35% after first contraction, ∼66% overall) compared to an abrupt drop in mdx upon the first eccentric contraction (∼73% after first contraction, ∼89% after three contractions). In dKO protection from eccentric contraction damage was linked with a doubling of SERCA1 pump density the EDL. We propose that the increased oxidative metabolism of fast-twitch glycolytic fibres characteristic of the null polymorphism (R577X) and increase in SR Ca2+ pump proteins reduces muscle fibre branching and decreases susceptibility to eccentric injury in the dystrophinopathies.

BACKGROUND AND PURPOSE The purpose of this study was to determine the role of NaV 1.7 in action potential conduction in C-fibres in the bronchial branches of the human vagus nerve. EXPERIMENTAL APPROACH Bronchial branches of the vagus nerve were dissected from human donor tissue. The C-wave of the electrically evoked compound action potential was quantified in the absence and presence of increasing concentrations of the selective NaV 1.7 blocking drugs, PF-05089771 and ST-2262, as well as the NaV 1.1, 1.2, and 1.3 blocking drug ICA121-431. The efficacy and potency of these inhibitors were compared to the standard NaV 1 blocker, tetrodotoxin. We then compared the relative potencies of the NaV 1 blockers in inhibiting the C-wave of the compound action potential, with their ability to inhibit parasympathetic cholinergic contraction of human isolated bronchi, a response previously shown to be strictly dependent on NaV 1.7 channels. KEY RESULTS The selective NaV 1.7 blockers inhibited the C-wave of the compound action potential with potencies similar to that observed in the NaV 1.7 bronchial contractions assay. Using rt-PCR, we noted that NaV 1.7 mRNA was strongly expressed and transported down the vagus nerve bundles. CONCLUSIONS AND IMPLICATIONS NaV 1.7 blockers can prevent action potential conduction in the majority of vagal C-fibres arising from human bronchi. Blockers of NaV 1.7 channels may therefore have value in inhibiting the responses to excessive airway C-fibre activation in inflammatory airway disease, responses that include coughing as well as reflex bronchoconstriction and secretions.

The imbalance of vasoconstrictor and vasodilator axes of the renin-angiotensin system (RAS) is observed in hypertension. Exercise regulates RAS level and improves vascular function. This study focused on the contribution of RAS axes in vascular function of mesenteric arteries and exercise-induced DNA methylation of the Agtr1a (AT1aR) and Mas1 (MasR) genes in hypertension. Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats were randomized into exercise or sedentary group. Levels of plasma RAS components, vascular tone, and DNA methylation markers were measured. Blood pressure of SHR was markedly reduced after 12 weeks of aerobic exercise. RAS peptides in plasma were all increased with an imbalanced upregulation of Ang II and Ang-(1–7) in SHR, exercise revised the level of RAS and increased Ang-(1–7)/Ang II. The vasoconstriction response induced by Ang II was mainly via type 1 receptors (AT1R), while this contraction was inhibited by Mas receptor (MasR). mRNA and protein of AT1R and MasR were both upregulated in SHR, whereas exercise significantly suppressed this imbalanced increase and increased MasR/AT1R ratio. Exercise hypermethylated Agtr1a and Mas1 genes, associating with increased DNMT1 and DNMT3b and SAM/SAH. Aerobic exercise ameliorates vascular function via hypermethylation of the Agtr1a and Mas1 genes and restores the vasoconstrictor and vasodilator axes balance.

We have investigated the relative roles of α1-adrenoceptors and purinoceptors in contractions to low and high frequency stimulation of the mouse vas deferens, in terms of the time course of responses. In separate experiments, isometric contractile responses were obtained to 10 pulses at 1 Hz and 40 pulses at 10 Hz. Responses to 1 Hz stimulation consisted of a series of discrete peaks. The α1A-adrenoceptor antagonist RS100329 (10-9M-10-7M) significantly reduced the response to the first pulse, the α1D-adrenoceptor antagonist BMY7378 (10-7M-10-6M) significantly reduced the response to the first two pulses, and the non-selective α1-adrenoceptor antagonist prazosin (10-8M) reduced the response to the first 4 pulses at 1 Hz. Responses to 10 Hz stimulation consisted of an early peak response and a maintained plateau response. RS100329 significantly reduced the peak response but did not significantly affect the plateau response. Prazosin, significantly reduced both the peak and plateau responses. The α1A-adrenoceptor antagonist RS17053 in high concentrations reduced mainly the plateau response leaving a clear early peak response. The plateau response of contraction was almost abolished by the purinoceptor antagonist suramin. These results suggest that there is a relatively minor early α1D-adrenoceptor and a larger early α1A-adrenoceptor component to stimulationevoked contractions of mouse vas deferens, but the major α1-adrenoceptor component is revealed by prazosin to be α1B-adrenoceptor mediated. α1B-Adrenoceptor activation probably facilitates contractions mediated by other α1-adrenoceptors and by purinoceptors. These results suggest that combined non-selective α1-adrenoceptor blockade, particularly α1B-adrenoceptor blockade, in addition to P2X1-purinoceptor blockade is useful in reducing male fertility.

Background Gastroesophageal reflux disease (GERD) is associated with lower esophageal sphincter (LES) incompetence. In some patients, GERD is refractory to acid reduction therapy which is the main treatment for GERD. So far, medications that can increase LES tone are few. Arecae pericarpium (A. pericarpium) is a medication in Traditional Chinese Medicine known to promote intestinal motility. Methods We investigated the effect of A. pericarpium extracts on porcine LES motility. In addition, we used tetrodotoxin (TTX) and atropine to study the underlying mechanism of A. pericarpium extracts-induced contractions of LES. Results The results of this study showed that A. pericarpium extracts and their main active ingredient, arecoline, can induce the contractions of porcine LES sling and clasp muscles in a dose-response manner. TTX did not have an inhibitory effect on the contractions induced by A. pericarpium extracts and arecoline in LES. However, atropine significantly inhibited A. pericarpium extracts- and arecoline-induced contractions of LES. Conclusion A. pericarpium extracts can induce the contractions of porcine LES in a dose dependent manner, possibly through muscarinic receptors, and hence, may be worth developing as an alternative therapy for GERD.

Neuromuscular electrical stimulation (NMES) can be delivered in a conventional form (CONVNMES) and using relatively wide-pulses and high-frequencies (WPHFNMES). WPHFNMES is proposed to reduce contraction fatigability and generate larger contractions with less discomfort than CONVNMES; however, there are no systematic reviews to guide the selection of NMES types. This systematic review compared the effects of CONVNMES versus WPHFNMES on contraction fatigability, strength adaptations, and perceived discomfort in clinical and non-clinical populations. Eight studies were included. When averaged across all non-clinical participants in individual short- and long-term studies, there was either no difference between CONVNMES and WPHFNMES for all outcomes or WPHFNMES produced more fatigability. In a subset of non-clinical participants (“responders”), however, WPHFNMES reduced contraction fatigability during a single session. Long-term studies found no differences between protocols for strength adaptations in non-clinical participants and those with multiple sclerosis. We concluded that WPHFNMES reduces contraction fatigability only in the short-term studies and in non-clinical responder participants and may exacerbate fatigability in non-responders. This review was registered in the prospective international registry of systematic reviews/PROSPERO (Registration Number: CRD42020153907). Novelty: WPHF NMES may reduce fatigue in some participants and exacerbate fatigue in others. There were no differences in long-term studies between WPHF and CONV NMES on strength adaptations. Future high-quality research is needed to optimize outcomes of NMES-based programs.

Near-infrared spectroscopy (NIRS) signals quantify the oxygenated (ΔHbMbO(2)) and deoxygenated (ΔHHbMb) heme group concentrations. ΔHHbMb has been preferred to ΔHbMbO(2) in evaluating skeletal muscle oxygen extraction because it is assumed to be less sensitive to blood volume (BV) changes, but uncertainties exist on this assumption. To analyze this assumption, a computational model of oxygen transport and metabolism is used to quantify the effect of O(2) delivery and BV changes on the NIRS signals from a canine model of muscle oxidative metabolism (Sun Y, Ferguson BS, Rogatzki MJ, McDonald JR, Gladden LB. Med Sci Sports Exerc 48: 2013–2020, 2016). The computational analysis accounts for microvascular (ΔHbO(2), ΔHHb) and extravascular (ΔMbO(2), ΔHMb) oxygenated and deoxygenated forms. Simulations predicted muscle oxygen uptake and NIRS signal changes well for blood flows ranging from resting to contracting muscle. Additional NIRS signal simulations were obtained in the absence or presence of BV changes corresponding to a heme groups concentration changes (ΔHbMb = 0–48 µM). Under normal delivery (Q = 1.0 L·kg(−1)·min(−1)) in contracting muscle, capillary oxygen saturation (So(2)) was 62% with capillary ΔHbO(2) and ΔHHb of ± 41 µΜ for ΔHbMb = 0. An increase of BV (ΔHbMb = 24 µΜ) caused a ΔHbO(2) decrease (16µΜ) almost twice as much as the increase observed for ΔHHb (9 µΜ). When So(2) increased to more than 80%, only ΔHbO(2) was significantly affected by BV changes. The analysis indicates that microvascular So(2) is a key factor in determining the sensitivity of ΔHbMbO(2) and deoxygenated ΔHHbMb to BV changes. Contrary to a common assumption, the ΔHHbMb is affected by BV changes in normal contracting muscle and even more in the presence of impaired O(2) delivery. NEW & NOTEWORTHY Deoxygenated is preferred to the oxygenated near-infrared spectroscopy signal in evaluating skeletal muscle oxygen extraction because it is assumed to be insensitive to blood volume changes. The quantitative analysis proposed in this study indicates that even in absence of skin blood flow effects, both NIRS signals in presence of either normal or reduced oxygen delivery are affected by blood volume changes. These changes should be considered to properly quantify muscle oxygen extraction by NIRS methods.

Objective In the present study, we sought to investigate the in vivo musculoaponeurotic architecture of the masseter muscle (MM) volumetrically with ultrasound in asymptomatic participants. It was hypothesized that the mean fiber bundle length (FBL) and mean aponeurotic height of laminae of the MM differ significantly between the relaxed state and maximally contracted state upon elevation of the mandible. Study Design The MM was investigated volumetrically in 12 male and 12 female asymptomatic participants (mean age, 25.8 ± 4.1 years) using ultrasound. The mean FBL and mean height of aponeuroses in the relaxed and maximally contracted states were compared using paired t tests, with significance established at P ≤ .05. Intrarater reliability was assessed using the intraclass correlation coefficient (ICC). Results The MM consisted of the superficial head (SH) and deep head, each arranged in multiple laminae. Fiber bundles extended between superior and inferior aponeuroses and/or bone. Statistically significant differences (P ≤ .05) were observed in mean FBL and in mean height of aponeuroses between the relaxed and contracted states only in superficial laminae of the SH. Conclusions These results suggest there is differential contraction of the laminae of the MM in the transition from relaxed to contracted states. Future comparison with pathologic patients can be made on the basis of an established normative database.

KEY POINTS The functional role of motor cortical reorganization following spinal cord injury (SCI) remains largely unknown. Here, we tested motor maps in a hand muscle at rest and during voluntary contraction of the hand with and without voluntary contraction of a proximal arm muscle. Motor map area in participants with SCI decreased during hand voluntary contraction and further decreased during additional contraction of a proximal arm muscle compared with rest. In contrast, motor map area in controls increased during the same motor tasks. Participants with SCI with more severe sensory deficits in the hand showed larger decreases in motor map area. Ten minutes of hand muscle-tendon vibration increased the motor map area during voluntary contraction in SCI participants. These novel findings suggest that abnormal changes in motor cortical maps during voluntary contraction after SCI can be reshaped by sensory input, knowledge that can have implications for rehabilitation. ABSTRACT Motor cortical representations reorganize following cervical spinal cord injury (SCI). The functional role of this reorganization remains largely unknown. Using neuronavigated transcranial magnetic stimulation, we examined motor cortical maps during voluntary contraction in humans with chronic cervical SCI and age-matched controls. We constructed motor maps in the first dorsal interosseous (FDI) muscle at rest and during voluntary contraction of the FDI with and without voluntary contraction of the biceps brachi (BB). The role of sensory input into this reorganization was examined by muscle-tendon vibration. We found that, at rest, motor maps were larger in SCI (22.3 cm2 ) compared with control (12.6 cm2 , P

Measures to reduce energy losses in pipeline transport systems must be implemented already at the design stage. In particular, this also applies to local resistances of pipelines. For symmetrical sudden pipe contraction, one of such measure is profiling using insert. The paper considers a sharp-edged pipe insert, which in comparison with others has larger areas of flow separation. The diameter of the insert was calculated as the arithmetic mean between the diameters forming the sudden pipe contraction. Using the methodology described in the literature, the contraction length ratio as the areas of influence between two symmetrical sudden contractions of a circular pipe during the flow of a single-phase turbulent flow of Newtonian fluid was investigated. The coefficient of mutual influence of these local resistances was determined by formulae for direct-flowing and non-direct-flowing locking devices, which simulated symmetrical and asymmetrical fluid flow after the constriction plane, respectively. The contraction rate from 0.064 to 0.696 inclusive are considered. According to the results of calculations, no mutual influence of two sudden contractions of circular pipe was found. This indicates the unsuitability of using formulae for locking devices in this methodology for determining the contraction length ratio. Therefore, to study this problem on the sudden pipe contraction with different contraction rates, it is proposed to conduct a physical experiment. In a mathematical experiment, you can use formulae to determine the following values: upstream recirculation length and downstream recirculation length; inlet length of cylindrical pipes with turbulized the flow devices; length of the velocity profile stabilization after local resistances.

Duchenne muscular dystrophy (DMD) is the second most common fatal genetic disease in humans and is characterized by the absence of a functional copy of the protein dystrophin from skeletal muscle. In dystrophin-negative humans and rodents, regenerated skeletal muscle fibers show abnormal branching. The number of fibers with branches and the complexity of branching increases with each cycle of degeneration/regeneration. Previously, using the mdx mouse model of DMD, we have proposed that once the number and complexity of branched fibers present in dystrophic fast-twitch EDL muscle surpasses a stable level, we term the “tipping point,” the branches, in and of themselves, mechanically weaken the muscle by rupturing when subjected to high forces during eccentric contractions. Here, we use the slow-twitch soleus muscle from the dystrophic mdx mouse to study prediseased “periambulatory” dystrophy at 2–3 wk, the peak regenerative “adult” phase at 6–9 wk, and “old” at 58–112 wk. Using isolated mdx soleus muscles, we examined contractile function and response to eccentric contraction correlated with the amount and complexity of regenerated branched fibers. The intact muscle was enzymatically dispersed into individual fibers in order to count fiber branching and some muscles were optically cleared to allow laser scanning confocal microscopy. We demonstrate throughout the lifespan of the mdx mouse that dystrophic slow-twitch soleus muscle is no more susceptible to eccentric contraction-induced injury than age-matched littermate controls and that this is correlated with a reduction in the number and complexity of branched fibers compared with fast-twitch dystrophic EDL muscles.

Epithelial cells use the process of extrusion to promote cell death while preserving a tight barrier. To extrude, a cell and its neighbors contract actin and myosin circumferentially and basolaterally to seamlessly squeeze it out of the epithelium. Recent research highlights how early apical pulsatile contractions within the extruding cell might orchestrate contraction in three dimensions so that a cell extrudes out apically. Along with apical constrictions, studies of ion channels and mathematical modeling reveal how differential contraction between cells helps select specific cells to extrude. In addition, several studies have offered new insights into pathways that use extrusion to eliminate transformed cells or cause an aberrant form of extrusion that promotes cell invasion.

Here we investigate mechanisms underlying spontaneous phasic contractions (SPCs) and sympathetic control of contractility in the rat epididymis, a long tubular duct involved in transportation and maturation of sperm. Longitudinal contractions of short segments (~ 1.5 mm) of rat proximal and distal caudal epididymal duct were measured + / − nerve stimulation. The extent of sympathetic innervation of these duct regions was determined by immunohistochemistry. Proximal caudal duct segments (150–300 μm dia.) exhibited SPCs, while distal segments (350–500 μm) were quiescent in ~ 80% of preparations. SPC amplitude and frequency were reduced by the L-type voltage-dependent Ca2+ channel (LVDCC) blocker nifedipine (1 μM), with the T-type voltage-dependent Ca2+ channel (TVDCC) blocker ML218 (1 μM) specifically decreasing SPC frequency. SPCs were inhibited upon blockade of the SR/ER Ca2+-ATPase (CPA 10 μM). SPCs were also inhibited by caffeine (1 μM), 2-APB (100 μM), niflumic acid (100 μM), or by lowering extracellular [Cl−] from 134.4 to 12.4 mM but not by ryanodine (25 μM) or tetracaine (100 μM). Electrical field stimulation (EFS) at 2 Hz for 60 s caused a sustained α1-adrenoceptor-sensitive contraction in distal segments and enhanced and/or induced α2-adrenoceptor-sensitive oscillatory phasic contractions in proximal and distal segments, the latter mimicked by application of the α2-adrenoceptor agonist clonidine. We hypothesise that SPCs in the proximal cauda are triggered by pacemaker mechanisms involving rhythmic IP3 receptor–operated SR/ER store Ca2+ release and resultant activation of CaCC with TVDCCs and possibly LVDCCs subserving in this process. Sympathetic nerve-released noradrenaline induces α2-adrenoceptor-mediated phasic contractions in the proximal and distal cauda. These findings provide new pharmacological targets for male infertility and contraception.

Aim: Given the high complication rates associated with orthognathic surgery for the correction of maxillomandibular malformations, studies have focused on alternative methods of strengthening the jaw, such as distraction osteogenesis. However, methods of shortening of the jaw are not well-elucidated in oral and maxillofacial surgery practice. This study aims to investigate the efficacy of a new method of shortening osteotomized jaws. Methodology: A 2.5–3 cm skin incision was made on the left tibia of each of 15 New Zealand white rabbits aged 12–18 months, followed by fixation of 15 mm pre-opened distractor devices to the tibia after osteotomy. After a five-day latency period, the distractors were activated to a total of 8 mm, with closure of the device set at a rate of 0.25 mm/day in the test group. After a five-day latency period, the distractors closed at a rate of 0.125 mm/day, achieving a total contraction of 5 mm. The distractors were not activated in the control group. The bone at the contraction range was evaluated, and the resultant shortening was measured. Results: The tibia was shortened by an average of 4.32 mm. Exaggerated bone formation was identified around the osteotomized cortical bone in all rabbits in the control and study groups, and there were minimal complication rates. Conclusion: This study verified that the jaw can be shortened by performing slow, controlled contraction with a bone resorption pattern. How to cite this article: Ocak H, Kılıç E. Alkan A, Shortening of the bones using a novel contraction osteogenesis device: An experimental study. Int Dent Res 2021;11(Suppl.1):26-31. https://doi.org/10.5577/intdentres.2021.vol11.suppl1.5 Linguistic Revision: The English in this manuscript has been checked by at least two professional editors, both native speakers of English.

Background Obesity increases and surgical weight reduction decreases the risk of atrial fibrillation (AF) and heart failure (HF). We hypothesized that surgically induced weight loss may favorably affect left atrial (LA) mechanical function measured by longitudinal strain, which has recently emerged as an independent imaging biomarker of increased AF and HF risk. Methods We retrospectively evaluated echocardiograms performed before and 12.2 ± 2.2 months after bariatric surgery in 65 patients with severe obesity (mean age 39 [36; 47] years, 72% of females) with no known cardiac disease or arrhythmia. The LA mechanical function was measured by the longitudinal strain using the semi-automatic speckle tracking method. Results After surgery, body mass index decreased from 43.72 ± 4.34 to 30.04 ± 4.33 kg/m2. We observed a significant improvement in all components of the LA strain. LA reservoir strain (LASR) and LA conduit strain (LASCD) significantly increased (35.7% vs 38.95%, p = 0.0005 and − 19.6% vs − 24.4%, p p = 0.0075). There was a significant correlation between an increase in LASR and LASCD and the improvement in parameters of left ventricular diastolic and longitudinal systolic function (increase in E’ and MAPSE). Another significant correlation was identified between the decrease in LASCT and an improvement in LA function (decrease in A’). Conclusions The left atrial mechanical function improves after bariatric surgery. It is partially explained by the beneficial effect of weight reduction on the left ventricular diastolic and longitudinal systolic function. This effect may contribute to decreased risk of AF and HF after bariatric surgery. Graphical abstract

In an integrative approach, we studied cardiac effects of recently published novel H2 receptor agonists in the heart of mice that overexpress the human H2 receptor (H2-TG mice) and littermate wild type (WT) control mice and in isolated electrically driven muscle preparations from patients undergoing cardiac surgery. Under our experimental conditions, the H2 receptor agonists UR-Po563, UR-MB-158, and UR-MB-159 increased force of contraction in left atrium from H2-TG mice with pEC50 values of 8.27, 9.38, and 8.28, respectively, but not in WT mice. Likewise, UR-Po563, UR-MB-158, and UR-MB-159 increased the beating rate in right atrium from H2-TG mice with pEC50 values of 9.01, 9.24, and 7.91, respectively, but not from WT mice. These effects could be antagonized by famotidine, a H2 receptor antagonist. UR-Po563 (1 µM) increased force of contraction in Langendorff-perfused hearts from H2-TG but not WT mice. Similarly, UR-Po563, UR-MB-158, or UR-MB-159 increased the left ventricular ejection fraction in echocardiography of H2-TG mice. Finally, UR-Po563 increased force of contraction in isolated human right atrial muscle strips. The contractile effects of UR-Po563 in H2-TG mice were accompanied by an increase in the phosphorylation state of phospholamban. In summary, we report here three recently developed agonists functionally stimulating human cardiac H2 receptors in vitro and in vivo. We speculate that these compounds might be of some merit to treat neurologic disorders if their cardiac effects are blocked by concomitantly applied receptor antagonists that cannot pass through the blood-brain barrier or might be useful to treat congestive heart failure in patients. SIGNIFICANCE STATEMENT Recently, a new generation of histamine H2 receptor (H2R) agonists has been developed as possible treatment option for Alzheimer’s disease. Here, possible cardiac (side) effects of these novel H2R agonists have been evaluated.

BACKGROUND To investigate a novel velopharyngeal squeeze maneuver (VPSM) and novel endoscopic pharyngeal contraction grade (EPCG) scale for the evaluation of pharyngeal motor function. METHODS During endoscopic examination of 77 post-irradiated nasopharyngeal carcinoma patients and control subjects, VPSM was rated and lateral pharyngeal wall movement graded with EPCG scale during swallowing. Pharyngeal constriction ratio (PCR) measured by videofluoroscopy was used for correlation. RESULTS VPSM and EPCG scale showed almost perfect intra-rater and inter-rater reliability (Kappa: >0.90). VPSM was present in 61% of patients suggesting good pharyngeal motor function. VPSM was predictive of EPCG scale (Wald statistic = 29.99, p

What is the central question of this study? Is there a critical threshold beyond which the loss of muscle contractility is regulated by the level of muscle activation during single-limb exercise of differing intensities and volumes? What is the main finding and its importance? Plateaus in the decline in muscle contractility during single-limb knee extension depended on both exercise volume and contraction intensity. A plateau was only evident with an increase in exercise volume. Muscle activation increased and did not decline despite substantial reductions in contractility. The findings indicate that the decrease in muscle contractility exhibited by resistance-trained men during the performance of submaximal isometric contractions with the knee extensors was not regulated by the level of muscle activation.Our study examined the influence of contraction intensity and exercise volume on changes in muscle contractility and activation of the knee extensor muscles. Maximal voluntary torque (MVT) and rate of change in torque, surface electromyograms, voluntary activation, V-waves and quadriceps resting twitch measures were assessed in 10 resistance-trained men during two experimental sessions. Each session began with an initial baseline series of contractions at a fixed intensity of 40% or 80% MVT. The 40%-only session continued with five contractions to task failure at 40% MVT. The 80% session continued with five contractions to failure each at 80%, 60% and 40% MVT. Greater reductions in MVT were observed during the baseline contractions of the 40%-only session compared with the 80% session at each matched-volume time point (P 0.05), with similar changes in twitch values (P 0.001). MVT and twitch values plateaued at each intensity during the 80% session and were significantly different across intensities: 80%60%40% (P 0.001). There were no differences for measures during the five contractions at 40% MVT performed on the different days, despite a greater volume of exercise performed prior to the 40% MVT during the 80% session. At each contraction intensity, a plateau in contractility loss was observed as more contractions were performed. We found that initial increases in muscle activation were maintained in the presence of increases in exercise volume and, in contrast to the critical-threshold hypothesis, did not decline in parallel with reductions in muscle contractility.

The lymphatics maintain fluid balance by returning interstitial fluid to veins via contraction/compression of vessel segments with check valves. Disruption of lymphatic pumping can result in a condition called lymphedema with interstitial fluid accumulation. Lymphedema treatments are often ineffective, which is partially attributable to insufficient understanding of specialized lymphatic muscle lining the vessels. This muscle exhibits cardiac-like phasic contractions and smooth muscle-like tonic contractions to generate and regulate flow. To understand the relationship between this sub-cellular contractile machinery and organ-level pumping, we have developed a multiscale computational model of phasic and tonic contractions in lymphatic muscle and coupled it to a lymphangion pumping model. Our model uses the sliding filament model (Huxley in Prog Biophys Biophys Chem 7:255–318, 1957) and its adaptation for smooth muscle (Mijailovich in Biophys J 79(5):2667–2681, 2000). Multiple structural arrangements of contractile components and viscoelastic elements were trialed but only one provided physiologic results. We then coupled this model with our previous lumped parameter model of the lymphangion to relate results to experiments. We show that the model produces similar pressure, diameter, and flow tracings to experiments on rat mesenteric lymphatics. This model provides the first estimates of lymphatic muscle contraction energetics and the ability to assess the potential effects of sub-cellular level phenomena such as calcium oscillations on lymphangion outflow. The maximum efficiency value predicted (40%) is at the upper end of estimates for other muscle types. Spontaneous calcium oscillations during diastole were found to increase outflow up to approximately 50% in the range of frequencies and amplitudes tested. Supplementary Information The online version contains supplementary material available at 10.1007/s10237-021-01501-0.

Cell signaling pathways regulating myosin regulatory light chain (LC20) phosphorylation contribute to determining contractile responses in smooth muscles. Following excitation and contraction, phasic smooth muscles, such as the digestive tract and urinary bladder, undergo relaxation due to a decline of cellular Ca2+ concentration and decreased Ca2+ sensitivity of LC20 phosphorylation, named Ca2+ desensitization. Here, we determined the mechanisms underlying the temporal Ca2+ desensitization of LC20 phosphorylation in phasic smooth muscles using permeabilized strips of the mouse ileum and urinary bladder. Upon stimulation with pCa6.0 at 20°C, contraction and LC20 phosphorylation peaked within 30 s and then declined to about 50% of the peak force at 2 min after stimulation. During the relaxation phase after the contraction, LC20 kinase [myosin light chain kinase (MLCK)] was inactivated, but no fluctuation in LC20 phosphatase activity occurred, suggesting that MLCK inactivation is a cause of the Ca2+-induced Ca2+ desensitization of LC20 phosphorylation. MLCK inactivation was associated with phosphorylation at the calmodulin-binding domain of the kinase. Treatment with STO-609 and TIM-063 antagonists for Ca2+/calmodulin (CaM)-dependent protein kinase kinase-β (CaMKKβ) attenuated both the phasic response of the contraction and MLCK phosphorylation, whereas neither CaM kinase II, AMP-activated protein kinase, nor p21-activated kinase induced MLCK inactivation in phasic smooth muscles. Conversely, protein phosphatase 2A inhibition amplified the phasic response. Signaling pathways through CaMKKβ and protein phosphatase 2A may contribute to regulating the phasic response of smooth muscle contraction.

Although unphysiological wall shear stress (WSS) has become the consensus hemodynamic mechanism for coronary atherosclerosis, the complex biomechanical stimulus affecting atherosclerosis evolution is still undetermined. This has motivated the interest on the contraction/expansion action exerted by WSS on the endothelium, obtained through the WSS topological skeleton analysis. This study tests the ability of this WSS feature, alone or combined with WSS magnitude, to predict coronary wall thickness (WT) longitudinal changes. Nine coronary arteries of hypercholesterolemic minipigs underwent imaging with local WT measurement at three time points: baseline (T1), after 5.6 ± 0.9 (T2), and 7.6 ± 2.5 (T3) months. Individualized computational hemodynamic simulations were performed at T1 and T2. The variability of the WSS contraction/expansion action along the cardiac cycle was quantified using the WSS topological shear variation index (TSVI). Alone or combined, high TSVI and low WSS significantly co-localized with high WT at the same time points and were significant predictors of thickening at later time points. TSVI and WSS magnitude values in a physiological range appeared to play an atheroprotective role. Both the variability of the WSS contraction/expansion action and WSS magnitude, accounting for different hemodynamic effects on the endothelium, (1) are linked to WT changes and (2) concur to identify WSS features leading to coronary atherosclerosis.

Background There exists contradictory evidence that states both the beneficial and deleterious effects of caffeine on wound healing. The general population might unknowingly consume caffeine that negatively affects wound healing. The main objective of this study is to investigate the effect of daily caffeine consumption on wound healing, specifically full-thickness skin graft (FTSG). Methods Forty Sprague–Dawley rats were randomized into four groups of equal size: control-dose (CD), low-dose (LD), medium-dose (MD), and high-dose (HD) caffeine groups. After autologous FTSG, all subjects in the intervention group were given daily pure caffeine gavage. The FTSG was explanted 7 days posttransplant. The graft viability, secondary contraction, and adherence were evaluated macroscopically, while fibroblast and collagen deposition was analyzed microscopically with hematoxylin eosin stain. Results The least graft viability (72.8 ± 20.7%, clinical wound assessment scale [CWAS] 2.4), highest secondary contraction (11.4 ± 10.5%), and fibroblast count (331.8 ± 88.6 cells/5 high power fields) were observed in the MD group. More collagen synthesis was observed in subjects who consumed caffeine. The level of secondary contraction, fibroblast count as well as graft viability and collagen synthesis were positively correlated. Conclusions Daily consumption of caffeine impairs graft viability when given in medium dose and increases collagen synthesis, irrespective of dosage. This study was in experimental rats; the results are not directly translatable to humans.

In this short manuscript, we revisit the renowned contraction’s of Meir-Keeler by involving the interpolation theory in the context of complete metric space. We provide a simple example to illustrate the validity of the observed result

Identifying the factors that contribute to individual differences in mid-level intensity neuromuscular fatigue is essential to improve performance and effective exercise in training and rehabilitation. This study investigated factors affecting individual differences in knee extensor fatigue induced by sustained isometric mid-level contractions. Twenty-six healthy young men performed a sustained fatiguing contraction to task failure at 40% maximal voluntary contraction (MVC) torque of the knee extensors. The MVC torque (TQMVC), evoked triplet torque (TQTRI), and voluntary activation (VA%) of the knee extensors were determined before and after the fatiguing task. Differences in TQMVC, TQTRI, and VA% before and after the fatiguing task were examined, and the relationship between TQMVC and TQTRI or VA% after the fatiguing task normalized to baseline was examined using Pearson product-moment correlation analysis. TQMVC and TQTRI decreased significantly after the fatiguing task (31.1% decrease for TQMVC, 38.8% decrease for TQTRI, p < 0.001), whereas VA% did not change significantly (4.2% increase for VA%, p = 0.057). After the fatiguing task, the normalized TQMVC was significantly correlated with the normalized TQTRI (r = 0.617, p < 0.001), but not with the normalized VA% (r = 0.348, p = 0.082). Individual differences in knee extensor fatigue induced by sustained mid-level contraction were more affected by peripheral fatigue than by central fatigue. Therefore, focusing on fatigue resistance in peripheral areas is important to improve endurance in moderate-intensity exercises.

It has been suggested that curvature progression in adolescent idiopathic scoliosis occurs through irreversible changes in the intervertebral discs. Strains of mice have been identified who differ in their disc wedging response upon extended asymmetrical compression. Annulus fibrosus tissue remodeling could contribute to the faster disc wedging progression previously observed in these mice. Differences in collagen remodeling capacity of annulus fibrosus cells between these in-bred mice strains was compared using an in vitro micro-tissue system. Annulus fibrosus cells of 8-10 week-old LG/J ("fast-healing") and C57BL/6J ("normal healing") mice were embedded in a micro-tissue platform and cultured for 48 hours. Hereafter, tissues were partially released and cultured for another 96 hours. Micro-tissue surface area and waistcoat contraction, collagen orientation and collagen content were measured. After 96 hours post-release, micro-tissues with annulus fibrosus cells of LG/J mice showed more surface area contraction (p < 0.001) and waistcoat contraction (p = 0.002) than C57BL/6J micro-tissues. Collagen orientation did not differ at 24 hours after partial release. However, at 96 hours, collagen in the micro-tissues from LG/J annulus fibrosus cells was aligned more than in those from C57BL/6J mice (p < 0.001). Collagen content did not differ between micro-tissues at 96 hours. Annulus fibrosus cells of inbred LG/J mice were better able to remodel and realign their collagen fibers than those from C57BL/6J mice. The remodeling of annulus fibrosus tissue could be contributing to the faster disc wedging progression observed in LG/J mice. This article is protected by copyright. All rights reserved.