The value of myocardial contraction fraction and long-axis strain to predict late gadolinium enhancement in multiple myeloma patients with secondary cardiac amyloidosis.

The aim of this study is to assess the effectiveness of conventional and two additional functional markers derived from standard cardiac magnetic resonance (CMR) images in detecting the occurrence of late gadolinium enhancement (LGE) in patients with secondary cardiac amyloidosis (CA) related to multiple myeloma (MM). This study retrospectively included 32 patients with preserved ejection fraction (EF) who had MM-CA diagnosed consecutively. Conventional left ventricular (LV) function markers and two additional functional markers, namely myocardial contraction fraction (MCF) and LV long-axis strain (LAS), were obtained using commercial cardiac post-processing software. Logistic regression analyses and receiver operating characteristic (ROC) analysis were performed to evaluate the predictive performances. (1) There were no notable distinctions in clinical features between the LGE+ and LGE- groups, with the exception of a reduced systolic blood pressure in the former (105.60 ± 18.85 mmHg vs. 124.50 ± 20.95 mmHg, P = 0.022). (2) Patients with MM-CA presented with intractable heart failure with preserved ejection fraction (HFpEF). The LVEF in the LGE+ group exhibited a greater reduction (54.27%, IQR 51.59-58.39%) in comparison to the LGE- group (P < 0.05). And MM-CA patients with LGE+ had significantly higher LVMI (90.15 ± 23.69 g/m2), lower MCF (47.39%, IQR 34.28-54.90%), and the LV LAS were more severely damaged (- 9.94 ± 3.42%) than patients with LGE- (all P values < 0.05). (3) The study found that MCF exhibited a significant independent association with LGE, as indicated by an odds ratio of 0.89 (P < 0.05). The cut-off value for MCF was determined to be 64.25% with a 95% confidence interval ranging from 0.758 to 0.983. The sensitivity and specificity of this association were calculated to be 95% and 83%, respectively. MCF is a simple reproducible predict marker of LGE in MM-CA patients. It is a potentially CMR-based method that promise to reduce scan times and costs, and boost the accessibility of CMR.

Immunomodulatory imide drugs inhibit human detrusor smooth muscle contraction and growth of human detrusor smooth muscle cells, and exhibit vaso-regulatory functions.

BACKGROUND: The immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC). METHODS: Cell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, RESULTS: Depending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50 %, while non-cholinergic contractions were inhibited up to 80 % and 60 % for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75 %. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization. CONCLUSIONS: IMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.

Development and characterization of contraction-suppressed full-thickness skin wound model in rabbits.

The wound healing process in rodents (rats and mice) and lagomorphs (rabbits) predominantly relies on wound contraction rather than re-epithelialization and granulation tissue formation. As a result, existing laboratory animal models for wound healing often fail to mimic human wound healing mechanisms accurately. This study introduces a standardized rabbit model with superior translational potential for skin wound healing research. Two full-thickness dermal wounds were created on the posterior dorsal surface of each rabbit using a standard 2 ×2 cm² template. One of these wounds was randomly selected to be treated as a contraction-suppressed wound by applying a transparent adhesive elastic bandage. At the same time, the other was retained as a standard full-thickness wound. Wound contraction was measured on 7, 14, 21, 28, and 35 days. Histomorphological evaluation was done on day 35 to evaluate the quality of wound healing. The findings indicate that transparent adhesive elastic bandage prolonged the wound healing time and suppressed wound contraction in rabbits. In addition, the healed contraction-suppressed full-thickness wounds had denser and thicker collagen fibers than the healed standard full-thickness wounds, indicating better collagen fiber deposition. Our model achieved a 100 % success rate in maintaining the transparent adhesive elastic bandage in the rabbits. Therefore, we have developed a simple, non-invasive, cost-effective method for preventing wound contraction. Further studies are required to establish the utility of this model for studying wound healing mechanisms and evaluating therapeutic interventions.

Assessment of Uterine Contraction and Atonic Bleeding during the Third Stage of Labor Using Shear Wave Elastography.

OBJECTIVE: This study aimed to clarify the relationship between fluctuations in uterine stiffness during the third stage of labor and blood loss upon placenta delivery using shear wave elastography. METHODS: This prospective cohort study enrolled consecutive singleton pregnant women above 37 weeks of gestation who delivered infants transvaginally at a single perinatal center. Shear wave velocities (SWV) were continuously measured during the third stage of transvaginal labor using transabdominal ultrasound and these values were compared between groups with large (≥500 g) and small amounts of bleeding during this stage. RESULTS: In total, 8 cases of large bleeding and 47 cases of small bleeding were compared. The large amount of bleeding group had a significantly lower median of minimum SWV values (0.97 [0.52-1.01] m/s than the small amount of bleeding group (1.25 [1.04-1.48] m/s p = 0.02). However, no significant differences were observed between the two groups in terms of median, mean, and maximum SWV values. The time from delivery of the infant to placental delivery was significantly longer in the large amount of bleeding group (median time: 370.5 s vs. 274 s, p < 0.05). CONCLUSION: Ultrasound quantification of uterine stiffness using shear wave elastography demonstrated that uterine contractions may influence the biological hemostasis of the uterus during the third stage of labor. Baseline uterine stiffness was weak and a longer duration of placental separation might be associated with cases of large amounts of bleeding during this stage.

DNA Base Damage Repair Crosstalks with Chromatin Structures to Contract Expanded GAA Repeats in Friedreich's Ataxia.

Trinucleotide repeat (TNR) expansion is the cause of over 40 neurodegenerative diseases, including Huntington's disease and Friedreich's ataxia (FRDA). There are no effective treatments for these diseases due to the poor understanding of molecular mechanisms underlying somatic TNR expansion and contraction in neural systems. We and others have found that DNA base excision repair (BER) actively modulates TNR instability, shedding light on the development of effective treatments for the diseases by contracting expanded repeats through DNA repair. In this study, temozolomide (TMZ) was employed as a model DNA base damaging agent to reveal the mechanisms of the BER pathway in modulating GAA repeat instability at the frataxin (FXN) gene in FRDA neural cells and transgenic mouse mice. We found that TMZ induced large GAA repeat contraction in FRDA mouse brain tissue, neurons, and FRDA iPSC-differentiated neural cells, increasing frataxin protein levels in FRDA mouse brain and neural cells. Surprisingly, we found that TMZ could also inhibit H3K9 methyltransferases, leading to open chromatin and increasing ssDNA breaks and recruitment of the key BER enzyme, pol ß, on the repeats in FRDA neural cells. We further demonstrated that the H3K9 methyltransferase inhibitor BIX01294 also induced the contraction of the expanded repeats and increased frataxin protein in FRDA neural cells by opening the chromatin and increasing the endogenous ssDNA breaks and recruitment of pol ß on the repeats. Our study provides new mechanistic insight illustrating that inhibition of H3K9 methylation can crosstalk with BER to induce GAA repeat contraction in FRDA. Our results will open a new avenue for developing novel gene therapy by targeting histone methylation and the BER pathway for repeat expansion diseases.

Research on joint synergy and muscle activity in ankle-foot complex motion.

The movement of the ankle-foot complex joints is coupled due to various physiological and physical constraints. This study introduces a novel approach to analyzing joint synergies and their physiological basis by focusing on joint rotational directions and the types of muscle contractions. We developed a biomimetic model of the ankle-foot complex with seven degrees of freedom, considering the skeletal configuration and physiological axis directions. Motion capture experiments were conducted with eight participants performing dorsiflexion and plantarflexion in open-chain states, as well as various walking tasks in closed-chain states, across different ground inclinations (±10°, ±5°, 0°) and walking speeds (3 km/h and 4 km/h). Hierarchical cluster analysis identified joint synergy clusters and motion primitives, revealing that in open-chain movements, plantarflexion of the ankle, tarsometatarsal, and metatarsophalangeal joints exhibited synergy with the inversion of the remaining joints in the complex; meanwhile, dorsiflexion was aligned with eversion. During closed-chain movements, the synergies grouping was exchanged in the subtalar, talonavicular, and metatarsophalangeal joints. Further analysis shows that in open-chain movements, synergy patterns influenced by multi-joint muscles crossing oblique joint axes contribute to foot motion. In closed-chain movements, these changes in synergetic patterns enhance the propulsion of the center of mass towards the contralateral leg and improve foot arch compliance, facilitating human motion. Our work enhances the understanding of the physiological mechanisms underlying synergistic motion within the ankle-foot complex.

Secret signal delayed mapping in patients with premature ventricular contractions.

Introduction: Mapping and radiofrequency ablation (RFA) of premature ventricular contractions (PVC) that show diurnal changes during the day, and which are rare during 3-D mapping has become very difficult. The most delayed signal mapping in the right ventricular outflow tract (RVOT) with RV apical pacing might be useful in these situations and we called this method Secret Signal Delayed Mapping (SSDM). Aim: To compare the classical RFA and SSDM in patients with PVC. Material and methods: A total of 60 patients with > 10% PVCs detected in 24-hour rhythm Holter recordings and admitted to the laboratory for RFA, 30 of whom underwent classical ablation according to the local activation time (LAT) and 30 of whom were included in the SSDM group, were included in our study. In patients who did not have enough PVCs during 3-D mapping, a catheter was placed in the right ventricle, and delayed signals after the ventricular electrogram (EGM) were collected by fixed pacing and such patients were included in the SSDM group. Results: In all patients, PVC originated from the RVOT. The mean follow-up time of the patients was 10.2 ±1.6 months. Recurrence was detected in 11 (36.6%) patients in the LAT group and 4 (13.3%) patients in the SSDM group. Signal earlyness in LAT mapping was significantly higher in the LAT group (p < 0.001). In the SSDM group, an average of 128 ±24 delayed signals were collected, the mean delayed signal time was 77.6 ±17.7 ms. In the SSDM group, the average distance between the earliest signal on the LAT and the most delayed signal on the SSDM was 4.8 ±1.2 mm. Conclusions: In the treatment of PVCs with RFA, the SSDM method can be used in addition to classical ablation.

Model-based interspecies interpretation of botulinum neurotoxin type A on muscle-contraction inhibition.

Botulinum neurotoxins (BoNTs) are commonly used in therapeutic and cosmetic applications. One such neurotoxin, BoNT type A (BoNT/A), has been studied widely for its effects on muscle function and contraction. Despite the importance of BoNT/A products, determining the blood concentrations of these toxins can be challenging. To address this, researchers have focused on pharmacodynamic (PD) markers, including compound muscle action potential (CMAP) and digit abduction scoring (DAS). In this study, we aimed to develop a probabilistic kinetic-pharmacodynamic (K-PD) model to interpret CMAP and DAS data obtained from mice and rats during the development of BoNT/A products. The researchers also wanted to gain a better understanding of how the estimated parameters from the model relate to the bridging of animal models to human responses. We used female Institute of Cancer Research mice and Sprague-Dawley (SD) rats to measure CMAP and DAS levels over 32 weeks after administering BoNT/A. We developed a muscle-contraction inhibition model using a virtual pharmacokinetic (PK) compartment combined with an indirect response model and performed model diagnostics using goodness-of-fit analysis, visual predictive checks (VPC), and bootstrap analysis. The CMAP and DAS profiles were dose-dependent, with recovery times varying depending on the administered dose. The final K-PD model effectively characterized the data and provided insights into species-specific differences in the PK and PD parameters. Overall, this study demonstrated the utility of PK-PD modeling in understanding the effects of BoNT/A and provides a foundation for future research on other BoNT/A products.

A validation study of the accuracy of the atrial pace map assessed with intracardiac pattern matching: Potential utility of non-pulmonary vein mapping.

BACKGROUND: Identification of infrequent nonpulmonary vein trigger premature atrial contractions (PACs) is challenging. We hypothesized that pace mapping (PM) assessed by correlation scores calculated by an intracardiac pattern matching (ICPM) module was useful for locating PAC origins, and conducted a validation study to assess the accuracy of ICPM-guided PM. METHODS: Analyzed were 30 patients with atrial fibrillation. After pulmonary vein isolation, atrial pacing was performed at one or two of four sites on the anterior and posterior aspects of the left atrium (LA, n = 10/10), LA septum (n = 10), and lateral RA (n = 10), which was arbitrarily determined as PAC. The intracardiac activation obtained from each pacing was set as an ICPM reference consisting of six CS unipolar electrograms (CS group) or six CS unipolar electrograms and four RA electrograms (CS-RA group). RESULTS: The PM was performed at 193 ± 107 sites for each reference pacing site. All reference pacing sites corresponded to sites where the maximal ICPM correlation score was obtained. Sites with a correlation score ≥98% were rarely obtained in the CS-RA than CS group (33% vs. 55%, P = .04), but those ≥95% were similarly obtained between the two groups (93% vs. 88%, P = .71), and those ≥90% were obtained in all. The surface areas with correlation scores ≥98% (0[0,10] vs. 10[0,35] mm2, P = .02), ≥95% (10[10,30] vs. 50[10,180] mm2, P = .002) and ≥90% (60[30,100] vs. 170[100,560] mm2, P = .0002) were smaller in the CS-RA than CS group. CONCLUSIONS: ICPM-guided PM was useful for identifying the reference pacing sites. Combined use of RA and CS electrograms may improve the mapping quality.

Apnoea as a novel method to improve exercise performance: A current state of the literature.

Acute breath-holding (apnoea) induces a spleen contraction leading to a transient increase in haemoglobin concentration. Additionally, the apnoea-induced hypoxia has been shown to lead to an increase in erythropoietin concentration up to 5 h after acute breath-holding, suggesting long-term haemoglobin enhancement. Given its potential to improve haemoglobin content, an important determinant for oxygen transport, apnoea has been suggested as a novel training method to improve aerobic performance. This review aims to provide an update on the current state of the literature on this topic. Although the apnoea-induced spleen contraction appears to be effective in improving oxygen uptake kinetics, this does not seem to transfer into immediately improved aerobic performance when apnoea is integrated into a warm-up. Furthermore, only long and intense apnoea protocols in individuals who are experienced in breath-holding show increased erythropoietin and reticulocytes. So far, studies on inexperienced individuals have failed to induce acute changes in erythropoietin concentration following apnoea. As such, apnoea training protocols fail to demonstrate longitudinal changes in haemoglobin mass and aerobic performance. The low hypoxic dose, as evidenced by minor oxygen desaturation, is likely insufficient to elicit a strong erythropoietic response. Apnoea therefore does not seem to be useful for improving aerobic performance. However, variations in apnoea, such as hypoventilation training at low lung volume and repeated-sprint training in hypoxia through short end-expiratory breath-holds, have been shown to induce metabolic adaptations and improve several physical qualities. This shows promise for application of dynamic apnoea in order to improve exercise performance. HIGHLIGHTS: What is the topic of this review? Apnoea is considered as an innovative method to improve performance. This review discusses the effectiveness of apnoea (training) on performance. What advances does it highlight? Although the apnoea-induced spleen contraction and the increase in EPO observed in freedivers seem promising to improve haematological variables both acutely and on the long term, they do not improve exercise performance in an athletic population. However, performing repeated sprints on end-expiratory breath-holds seems promising to improve repeated-sprint capacity.

Advances in induced pluripotent stem cell-derived cardiac myocytes: technological breakthroughs, key discoveries and new applications.

A transformation is underway in precision and patient-specific medicine. Rapid progress has been enabled by multiple new technologies including induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). Here, we delve into these advancements and their future promise, focusing on the efficiency of reprogramming techniques, the fidelity of differentiation into the cardiac lineage, the functional characterization of the resulting cardiac myocytes, and the many applications of in silico models to understand general and patient-specific mechanisms controlling excitation-contraction coupling in health and disease. Furthermore, we explore the current and potential applications of iPSC-CMs in both research and clinical settings, underscoring the far-reaching implications of this rapidly evolving field.

С60 fullerene protective effect against the rat muscle soleus trauma.

Muscle trauma is one of the most common body injuries. Severe consequences of muscle trauma are ischemic injuries of the extremities. It is known that the intensification of free radical processes takes place in almost most acute diseases and conditions, including muscle trauma. C60 fullerene (C60) with powerful antioxidant properties can be considered a potential nanoagent for developing an effective therapy for skeletal muscle trauma. Here the water-soluble C60 was prepared and its structural organization has been studied by the atomic force microscopy and dynamic light scattering techniques. The selective biomechanical parameters of muscle soleus contraction and biochemical indicators of blood in rats were evaluated after intramuscular injection of C60 1 h before the muscle trauma initiation. Analysis of the force muscle response after C60 injection (1 mg kg-1 dose) showed its protective effect against ischemia and mechanical injury at the level of 30 ± 2 % and 17 ± 1 %, accordingly, relative to the pathology group. Analysis of biomechanical parameters that are responsible for correcting precise positioning confirmed the effectiveness of C60 at a level of more than 50 ± 3 % relative to the pathology group. Moreover, a decrease in the biochemical indicators of blood by about 33 ± 2 % and 10 ± 1 % in ischemia and mechanical injury, correspondingly, relative to the pathology group occurs. The results obtained demonstrate the ability of C60 to correct the functional activity of damaged skeletal muscle.

Acute microtubule changes linked to DMD pathology are insufficient to impair contractile function or enhance contraction-induced injury in healthy muscle.

Duchenne muscular dystrophy (DMD) is marked by the genetic deficiency of the dystrophin protein in striated muscle whose consequence is a cascade of cellular changes that predispose the susceptibility to contraction injury central to DMD pathology. Recent evidence identified the proliferation of microtubules enriched in post-translationally modified tubulin as a consequence of dystrophins absence that increases the passive mechanics of the muscle fiber and the excess mechanotransduction elicited reactive oxygen species and calcium signals that promote contraction injury. Motivated by evidence that acutely normalizing the disease microtubule alterations reduced contraction injury in murine DMD muscle (mdx), here we sought the direct impact of these microtubule alterations independent of dystrophins absence and the multitude of other changes consequent to dystrophic disease. To this end we used acute pharmacologic (epithiolone-D, EpoD; 4 hours) or genetic (vashohibin-2 and small vasohibin binding protein overexpression via AAV9; 2 weeks) strategies to effectively model the proliferation of detyrosination enriched microtubules in the mdx muscle. Quantifying in vivo nerve evoked plantarflexor function we find no alteration in peak torque nor contraction kinetics in WT mice modeling these DMD relevant MT alterations. Quantifying the susceptibility to eccentric contraction injury we show EpoD treatment proffered a small but significant protection from contraction injury while VASH/SVBP had no discernable impact. We conclude that the disease dependent MT alterations act in concert with additional cellular changes to predispose contraction injury in DMD.

Key considerations for investigating and interpreting autophagy in skeletal muscle.

Skeletal muscle plays a crucial role in generating force to facilitate movement. Skeletal muscle is a heterogenous tissue composed of diverse fibers with distinct contractile and metabolic profiles. The intricate classification of skeletal muscle fibers exists on a continuum ranging from type I (slow-twitch, oxidative) to type II (fast-twitch, glycolytic). The heterogenous distribution and characteristics of fibers within and between skeletal muscles profoundly influences cellular signaling; however, this has not been broadly discussed as it relates to macroautophagy/autophagy. The growing interest in skeletal muscle autophagy research underscores the necessity of comprehending the interplay between autophagic responses among skeletal muscles and fibers with different contractile properties, metabolic profiles, and other related signaling processes. We recommend approaching the interpretation of autophagy findings with careful consideration for two key reasons: 1) the distinct behaviors and responses of different skeletal muscles or fibers to various perturbations, and 2) the potential impact of alterations in skeletal muscle fiber type or metabolic profile on observed autophagic outcomes. This review provides an overview of the autophagic profile and response in skeletal muscles/fibers of different types and metabolic profiles. Further, this review discusses autophagic findings in various conditions and diseases that may differentially affect skeletal muscle. Finally, we provide key points of consideration to better enable researchers to fine-tune the design and interpretation of skeletal muscle autophagy experiments.Abbreviation: AKT1: AKT serine/threonine kinase 1; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATG4: autophagy related 4 cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; CS: citrate synthase; DIA: diaphragm; EDL: extensor digitorum longus; FOXO3/FOXO3A: forkhead box O3; GAS; gastrocnemius; GP: gastrocnemius-plantaris complex; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MYH: myosin heavy chain; PINK1: PTEN induced kinase 1; PLANT: plantaris; PRKN: parkin RBR E3 ubiquitin protein ligase; QUAD: quadriceps; RA: rectus abdominis; RG: red gastrocnemius; RQ: red quadriceps; SOL: soleus; SQSTM1: sequestosome 1; TA: tibialis anterior; WG: white gastrocnemius; WQ: white quadriceps; WVL: white vastus lateralis; VL: vastus lateralis; ULK1: unc-51 like autophagy activating kinase 1.

Preclinical determination of wound-healing activity of halibut oil cream in rat model of burn wound.

This study investigated the effects of halibut oil cream, containing omega-3 fatty acids, vitamins A and D, and hydroxyproline, on burn wound healing in rats. Acute dermal toxicity tests confirmed its nontoxicity. Wistar rats were divided into five groups: a control, a positive control treated with silver sulfadiazine 1% (SSD), and three groups treated with 3%, 9%, and 27% halibut oil cream Formulation (HBOF). The SSD and HBOF groups showed significant healing improvements compared to the control. Histopathological analysis indicated increased collagen production in the HBOF groups, suggesting halibut oil cream's potential as a topical treatment for burn wounds.

Instability in Computational Models of Vascular Smooth Muscle Cell Contraction.

PURPOSE: Through their contractile and synthetic capacity, vascular smooth muscle cells (VSMCs) can regulate the stiffness and resistance of the circulation. To model the contraction of blood vessels, an active stress component can be added to the (passive) Cauchy stress tensor. Different constitutive formulations have been proposed to describe this active stress component. Notably, however, measuring biomechanical behaviour of contracted blood vessels ex vivo presents several experimental challenges, which complicate the acquisition of comprehensive datasets to inform complex active stress models. In this work, we examine formulations for use with limited experimental contraction data as well as those developed to capture more comprehensive datasets. METHODS: First, we prove analytically that a subset of constitutive active stress formulations exhibits unstable behaviours (i.e., a non-unique diameter solution for a given pressure) in certain parameter ranges, particularly for large contractile deformations. Second, using experimental literature data, we present two case studies where these formulations are used to capture the contractile response of VSMCs in the presence of (1) limited and (2) extensive contraction data. RESULTS: We show how limited contraction data complicates selecting an appropriate active stress model for vascular applications, potentially resulting in unrealistic modelled behaviours. CONCLUSION: Our data provide a useful reference for selecting an active stress model which balances the trade-off between accuracy and available biomechanical information. Whilst complex physiologically motivated models' superior accuracy is recommended whenever active biomechanics can be extensively characterised experimentally, a constant 2nd Piola-Kirchhoff active stress model balances well accuracy and applicability with sparse contractile data.

Postpartum acute myometritis suppresses expression of contraction-associated proteins in the gravid uterus.

Uterine atony is a major contributor to postpartum hemorrhage. We previously proposed the novel histological concept of postpartum acute myometritis (PAM) to elucidate the pathophysiology of uterine atony. This concept involves the infiltration of macrophages and neutrophils, as well as mast cell and complement activation in the myometrium. However, the pathological mechanism underlying uterine atony in the context of PAM remains unclear. Herein, we focused on uterine contraction-associated proteins (CAPs) including connexin 43 (Cx43), oxytocin receptors (OXR), prostaglandin receptors EP1, EP3, FP, and protease-activated receptor (PAR)-1. This follow-up study aimed to compare CAP expression between PAM and control groups. We selected 38 PAM subjects from the cases enrolled in our amniotic fluid embolism registry between 2011 and 2018. Control tissues from 10 parturients were collected during cesarean section. We stained the myometrial tissues with the following CAP markers, inflammatory cell markers, and other markers: Cx43, OXR, EP1, EP3, FP, PAR-1, C5a receptor, tryptase, neutrophil elastase, CD68, ß-actin, and Na+/K+-ATPase. The immunostaining-positive areas of Cx43, OXR, EP1, EP3, and FP standardized by ß-actin in the PAM tissue were significantly smaller than in the control group, whereas those of PAR-1 and Na+/K+-ATPase increased significantly in the PAM group. The Cx43- and OXR-positive areas correlated negatively with the immunostaining-positive cell numbers of CD68 and tryptase with halo, respectively. PAM may impair individual and synchronized myocyte contraction, leading to uterine atony refractory to uterotonics. Further cell-based studies are needed to elucidate the molecular mechanism by which inflammatory cells suppress CAP expression.

In Situ Triggered Self-Contraction Bioactive Microgel Assembly Accelerates Diabetic Skin Wound Healing by Activating Mechanotransduction and Biochemical Pathway.

Chronic nonhealing skin wounds, characterized by reduced tissue contractility and inhibited wound cell survival under hyperglycemia and hypoxia, present a significant challenge in diabetic care. Here, an advanced self-contraction bioactive core-shell microgel assembly with robust tissue-adhesion (SMART-EXO) is introduced to expedite diabetic wound healing. The SMART-EXO dressing exhibits strong, reversible adhesion to damaged tissue due to abundant hydrogen and dynamic coordination bonds. Additionally, the core-shell microgel components and dynamic coordination bonds provide moderate rigidity, customizable self-contraction, and an interlinked porous architecture. The triggered in situ self-contraction of the SMART-EXO dressing enables active, tunable wound contraction, activating mechanotransduction in the skin and promoting the optimal fibroblast-to-myofibroblast conversion, collagen synthesis, and angiogenesis. Concurrently, the triggered contraction of SMART-EXO facilitates efficient loading and on-demand release of bioactive exosomes, contributing to re-epithelialization and wound microenvironment regulation in diabetic mice. RNA-seq results reveal the activation of critical signaling pathways associated with mechanosensing and exosome regulation, highlighting the combined biomechanical and biochemical mechanisms. These findings underscore SMART-EXO as a versatile, adaptable solution to the complex challenges of diabetic wound care.

Impact of Esophageal Motility on Microbiome Alterations in Symptomatic Gastroesophageal Reflux Disease Patients With Negative Endoscopy: Exploring the Role of Ineffective Esophageal Motility and Contraction Reserve.

Background/Aims: Ineffective esophageal motility (IEM) is common in patients with gastroesophageal reflux disease (GERD) and can be associated with poor esophageal contraction reserve on multiple rapid swallows. Alterations in the esophageal microbiome have been reported in GERD, but the relationship to presence or absence of contraction reserve in IEM patients has not been evaluated. We aim to investigate whether contraction reserve influences esophageal microbiome alterations in patients with GERD and IEM. Methods: We prospectively enrolled GERD patients with normal endoscopy and evaluated esophageal motility and contraction reserve with multiple rapid swallows during high-resolution manometry. The esophageal mucosa was biopsied for DNA extraction and 16S ribosomal RNA gene V3-V4 (Illumina)/full-length (Pacbio) amplicon sequencing analysis. Results: Among the 56 recruited patients, 20 had normal motility (NM), 19 had IEM with contraction reserve (IEM-R), and 17 had IEM without contraction reserve (IEM-NR). Esophageal microbiome analysis showed a significant decrease in microbial richness in patients with IEM-NR when compared to NM. The beta diversity revealed different microbiome profiles between patients with NM or IEM-R and IEM-NR (P = 0.037). Several esophageal bacterial taxa were characteristic in patients with IEM-NR, including reduced Prevotella spp. and Veillonella dispar, and enriched Fusobacterium nucleatum. In a microbiome-based random forest model for predicting IEM-NR, an area under the receiver operating characteristic curve of 0.81 was yielded. Conclusions: In symptomatic GERD patients with normal endoscopic findings, the esophageal microbiome differs based on contraction reserve among IEM. Absent contraction reserve appears to alter the physiology and microbiota of the esophagus.