Exploring the Impact of BKCa Channel Function in Cellular Membranes on Cardiac Electrical Activity.

This review paper delves into the current body of evidence, offering a thorough analysis of the impact of large-conductance Ca2+-activated K+ (BKCa or BK) channels on the electrical dynamics of the heart. Alterations in the activity of BKCa channels, responsible for the generation of the overall magnitude of Ca2+-activated K+ current at the whole-cell level, occur through allosteric mechanisms. The collaborative interplay between membrane depolarization and heightened intracellular Ca2+ ion concentrations collectively contribute to the activation of BKCa channels. Although fully developed mammalian cardiac cells do not exhibit functional expression of these ion channels, evidence suggests their presence in cardiac fibroblasts that surround and potentially establish close connections with neighboring cardiac cells. When cardiac cells form close associations with fibroblasts, the high single-ion conductance of these channels, approximately ranging from 150 to 250 pS, can result in the random depolarization of the adjacent cardiac cell membranes. While cardiac fibroblasts are typically electrically non-excitable, their prevalence within heart tissue increases, particularly in the context of aging myocardial infarction or atrial fibrillation. This augmented presence of BKCa channels' conductance holds the potential to amplify the excitability of cardiac cell membranes through effective electrical coupling between fibroblasts and cardiomyocytes. In this scenario, this heightened excitability may contribute to the onset of cardiac arrhythmias. Moreover, it is worth noting that the substances influencing the activity of these BKCa channels might influence cardiac electrical activity as well. Taken together, the BKCa channel activity residing in cardiac fibroblasts may contribute to cardiac electrical function occurring in vivo.

Exposure to bisphenol A associated with multiple health-related outcomes in humans: An umbrella review of systematic reviews with meta-analyses.

Bisphenol A (BPA), a toxic endocrine disruptor, is widely distributed in the environment, and the effects of BPA exposure on human health outcomes are a critical issue. The objective of this study was to perform an umbrella review of published meta-analyses investigating the associations between BPA exposure and human-related health outcomes. The relevant reports were searched from three electronic databases from inception to July 12, 2023 including PubMed, ScienceDirect, and Embase. The reports that were systematic reviews with meta-analyses investigating the associations between BPA exposure and human health outcomes were included in our review. A total of 14 reports were included in our review. Several human health outcomes related to exposure BPA were investigated including maternal prenatal health, infant health, allergic diseases, kidney disease, metabolic syndromes, polycystic ovary syndrome, earlier puberty, inflammation and immune responses, and thyroid function in neonates. Among these health outcomes, BPA exposure was associated with multiple human health outcomes including preterm birth, allergic diseases, kidney disease, polycystic ovarian syndrome, obesity, type 2 diabetes, cardiovascular disease, hypertension, and inflammation and immune responses (C-reactive protein and interleukin-6). These results showed that BPA exposure has seriously affected human health. To protect human health, World Health Organization should develop meaningful regulations on BPA to decrease the environmental contamination.

Extracorporeal Shock Wave Therapy Shows Superiority Over Injections for Pain Relief and Grip Strength Recovery in Lateral Epicondylitis: A Systematic Review and Network Meta-analysis.

PURPOSE: To examine the efficacy of extracorporeal shock wave therapy (ESWT) and injection therapies by synthesizing direct and indirect evidence for all pairs of competing therapies for lateral epicondylitis. METHODS: PubMed, EMBASE, and Web of Science databases were searched for all appropriate randomized controlled trials (RCTs), assessing the effect of ESWT or injection therapies. The primary outcome was short-term (≤3 months) and medium-term (>3 months but ≤12 months) pain, while the secondary outcomes were grip strength and patient-reported outcome measures. All outcomes were assessed using standardized mean differences (SMDs) with 95% confidence intervals (CIs) and were ranked using surface under the cumulative ranking curve (SUCRA) probabilities to determine a hierarchy of treatments. Sensitivity analysis was performed to eliminate potential therapeutic effects of normal saline (NS) and exclude trials that included patients with acute lateral epicondylitis (LE). RESULTS: 40 RCTs were included to evaluate ESWT and five different injection therapies, including corticosteroids (CSs), autologous whole blood, platelet-rich plasma (PRP), botulinum toxin A (BoNT-A), and dextrose prolotherapy (DPT). DPT (-.78 [-1.34 to -.21]), ESWT (.57 [-.89 to -.25]), PRP (-.48 [-.85 to -.11]), and BoNT-A (-.43 [-.84 to -.02]) outperformed placebo for short-term pain relief; ESWT (-.44 [-.85 to -.04]) outperformed placebo for medium-term pain relief. DPT was ranked as the most optimal short-term and medium-term pain reliever (SUCRA, 87.3% and 98.6%, respectively). ESWT was ranked as the most optimal short-term and medium-term grip strength recovery (SUCRA; 79.4% and 86.4%, respectively). CONCLUSIONS: DPT and ESWT were the best two treatment options for pain control and ESWT was the best treatment option for grip strength recovery. CSs were not recommended for the treatment of LE. More evidence is required to confirm the superiority in pain control of DPT among all these treatment options on LE. LEVEL OF EVIDENCE: Level I, meta-analysis of Level I randomized controlled trials.

Syndesmosis Changes before and after Syndesmotic Screw Removal: A Retrospective Radiographic Study.

BACKGROUND AND OBJECTIVES: In patients with ankle fractures complicated by syndesmotic injuries, no consensus has been reached on the best method of syndesmosis fixation using syndesmotic screws. One previous study revealed no difference in the tibiofibular overlap between two groups with or without syndesmotic screw removal. Other studies have indicated that distal tibiofibular diastasis exists after the removal of syndesmotic screws. In this study, we aimed to confirm the effect of syndesmotic screw removal on diastasis occurrence. We further analyzed the risk factors that may contribute to the widening of the tibiofibular syndesmosis. MATERIALS AND METHODS: This retrospective study involved a review of the records of 63 patients with ankle fractures accompanied by syndesmosis injuries that required syndesmotic screw fixation. Anteroposterior radiographs were analyzed for each patient at various time points, from syndesmotic screw fixation to outpatient department follow-ups after screw removal. The changes in tibia-fibula overlap (OL), tibia-fibula clear space (CS), and medial clear space (MCS) were analyzed. Further analysis was performed to reveal potential factors that may have contributed to radiographic differences. RESULTS: Compared with the postoperation radiographs following syndesmotic screw fixation, OL decreased (2.0 mm) and CS increased (0.8 mm) in the anteroposterior radiographs from outpatient department follow-ups. No significant changes were noted in OL or CS after syndesmotic screw removal. However, OL decreased (1.8 mm) and CS increased (0.5 mm) before syndesmotic screw removal. No significant change in MCS occurred during the whole observation period. Linear regression analysis did not reveal any significant correlations between potentially related factors and radiographic changes. CONCLUSIONS: Marked diastasis had occurred at final follow-up. Notably, the diastasis occurred before rather than after screw removal. This implies that screw removal does not significantly influence the radiographic outcomes of rotational ankle fractures.

Young Children with a Bucket-Handle Tear to the Discoid Lateral Meniscus Successfully Treated Using Arthroscopic Saucerization and Repair: Two Case Reports.

Observations of a symptomatic discoid lateral meniscus in young children are infrequent. The objective of this report was to demonstrate the use of arthroscopic saucerization and repair for treating a bucket-handle tear of a lateral discoid meniscus in two young children. Two young children (a 28-month-old girl and a 5-year-old boy) presented with a bucket-handle tear of the complete type lateral discoid meniscus. Both patients received arthroscopic saucerization and repair. A full knee extension under a long leg cast was applied for one month after surgery. The two patients were able to achieve a full range of motion of their operated knees without limping or presenting an antalgic gait at the third month after surgery. Both patients and their parents felt satisfied with the treatment at the 2- and 3-year follow-ups, respectively. Our results demonstrated that arthroscopic saucerization and repair seems to be an effective treatment for bucket-handle tears of the lateral discoid meniscus in young children-even those younger than 3 years old. We reported the youngest case (a 28-month-old girl) in comparison with the findings from a literature review.

Efficacy of different platelet-rich plasma injections in the treatment of mild-moderate knee osteoarthritis: A systematic review and meta-analysis.

AIMS: This study aimed to compare the efficacy of different numbered sets of injections of platelet-rich plasma (PRP) in the treatment of mild-moderate knee osteoarthritis (OA). METHODS: A comprehensive search in three databases of Cochrane Library, Embase, and PubMed was conducted to find relevant articles that investigated the efficacy of PRP injection therapies in the treatment of mild-moderate knee OA through August 2020. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores were the primary outcomes and visual analogue scale (VAS) was the secondary outcome. The pooled improvements amongst different injection therapies were compared. RESULTS: No significant differences in the improvement of WOMAC pain were observed amongst 1-, 2-, and 3-injection therapies at 3- (P = .26) and 6-month (P = .13) follow-ups. For a 12-month follow-up, the difference amongst different therapies reached borderline significance (P = .05) in which 3-injection therapy had a significantly better improvement than 2-injection therapy (P = .02) and reached borderline significance compared with 1-injection (P = .07). However, no significant differences in the improvement of VAS scores were observed amongst three injection therapies for all the follow-up visits (P > .05). For WOMAC function score, 3-injection therapy performed significantly better than 1-injection (P < .00001) or 2-injection therapy (P < .0001) only at 12-month follow-up visit. CONCLUSIONS: Our results demonstrated that 3-injection therapy of PRP in the treatment of mild-moderate knee OA had the best efficacy in pain relief and function improvement compared with 1- and 2-injection therapies.

Efficacy and Safety of Extracorporeal Shockwave Therapy for Treatment of Knee Osteoarthritis: A Systematic Review and Meta-analysis.

OBJECTIVE: The objective of this study was to assess the efficacy and safety of extracorporeal shockwave therapy (ESWT) for treatment of knee osteoarthritis (OA) using a systemic review and meta-analysis. METHODS: An extensive search of relevant articles from electronic databases Pubmed, Embase, and Cochrane Library from inception to March 2019 was conducted. The treatment outcomes (visual analog scale [VAS] and the Western Ontario and McMaster Universities Arthritis Index [WOMAC]) of the included articles were pooled to calculate effect sizes. The assessment of heterogeneity among articles was evaluated using I2. Statistical analyses were conducted using RevMan software. RESULTS: The results showed that the ESWT group had significant improvement in pain relief compared with the control group through 12 months based on WOMAC and VAS scores. Compared with the baseline level, the patients had significant improvement in pain relief at most follow-up points (one week to 12 months) based on WOMAC and VAS scores. The patients showed significant improvement in physical function at six- and 12-month follow-up when compared with the control group and for all follow-up (one to 12 months) when compared with the baseline level. Additionally, only minor complications were observed after ESWT treatment. CONCLUSIONS: The use of ESWT for treatment of knee OA had a beneficial effect on pain relief and physical function improvement for up to 12 months, and only minor complications occurred after ESWT treatment. However, there remains a lack of clarity regarding the frequency and dosage levels of ESWT required to achieve the maximum improvement.

Comparative effectiveness of various treatment strategies for trigger finger by pairwise meta-analysis.

OBJECTIVE: To compare the efficacy of various strategies in the treatment of trigger finger. DATA SOURCES: A systematic literature search for randomized controlled trials to compare treatments for trigger finger was conducted through three online databases, Pubmed, Embase and Cochrane Library, from their inception dates to 22 May 2020. METHODS: Relative risk (RR) with 95% confidence interval (CI) was used to evaluate the effect sizes in success rate for included articles. RESULTS: Sixteen articles (n = 1185) were included in our meta-analysis. The results showed that the efficacy of steroid injection was significantly better than the placebo group at short-term follow-ups (RR = 19.00, 95% CI = 1.17-309.77 for one-week; RR = 3.70, 95% CI = 3.70, 95% CI = 1.61-8.53 for one-month), and then became non-significant at four months (RR = 3.21, 95% CI = 0.88-11.79). There was no significant difference in success rate between steroid injection and nonsteroidal anti-inflammatory drug injection, and between open surgery and percutaneous release at all the follow-ups. Only surgical treatment had significantly better efficacy in success rate than steroid injection at all follow-ups (RR = 0.48, 95% CI = 0.34-0.66 for one-month; RR = 0.87, 95% CI = 0.80-0.96 for three-month; RR = 0.58, 95% CI = 0.48-0.68 for six-month; RR = 0.38, 95% CI = 0.20-0.72 for 12-month). CONCLUSION: There were no differences in efficacy between steroid injection and shockwave or nonsteroidal anti-inflammatory drug injection. The surgical treatments had the best efficacy among these treatments.

Clinical Outcomes of Total Ankle Arthroplasty Versus Ankle Arthrodesis for the Treatment of End-Stage Ankle Arthritis in the Last Decade: a Systematic Review and Meta-analysis.

Ankle arthrodesis (AA) and total ankle arthroplasty (TAA) are the 2 primary surgical treatments for patients with end-stage ankle arthritis. The comparative outcomes between AA and TAA using modern techniques remain unclear. A systematic search to identify all relevant articles comparing AA with TAA was conducted through 3 online databases. The clinical outcomes were extracted for meta-analysis, including AOFAS (American Orthopaedic Foot & Ankle Society) score, VAS (visual analog scale), AOS (Ankle Osteoarthritis Scale), gait analysis, ROM (range of motion), satisfaction, complication, and reoperation. Our meta-analysis shows no heterogeneity in any subgroup analyses. There were no significant differences in AOFAS total, pain, and alignment scores between the AA and TAA groups. The TAA group had significant improvement in AOFAS function score compared with the AA group. There was no significant difference in VAS and AOS total scores between the 2 groups. No significant differences in gait analysis were observed between the 2 groups. The TAA group had significant improvement in both ROM and change in ROM compared with the AA group. There was no significant difference in satisfaction rate between the 2 groups. The TAA group had significantly higher complication and reoperation rates compared with the AA group. Our meta-analysis provides updated evidence on clinical outcomes comparing AA with TAA using third-generation implants. The TAA group had better improvement in AOFAS function and ROM than the AA group. No significant differences in pain relief, gait analysis, or patient satisfaction were observed between the 2 groups.

Assessing the Similarity between Random Copolymer Drug Glatiramer Acetate by Using LC-MS Data Coupling with Hypothesis Testing.

The full characterization of nonbiological complex drugs (NBCDs) is not possible, but analytical approaches are of urgent need to evaluate the similarity between different lots and compare with their follow-up versions. Here, we propose a hypothesis testing-based approach to assess the similarity/difference between random amino acid copolymer drugs using liquid chromatography mass spectrometry (LC-MS) analysis. Two glatiramer acetate (GA) drugs, commercially available Copaxone and in-house synthesized SPT, and a negative control were digested by Lys-C and followed by HILIC-MS analysis. After retention time alignment and feature identification, 1627 features matched to m/z values in an elemental composition database were considered as derived from active drug ingredients. A hypothesis testing approach, the sum of squared deviations test, was developed to process high-dimensional data derived from LC-MS spectra. The feasibility of this approach was first demonstrated by testing 5 versus 5 lots of Copaxone and Copaxone versus SPT, which suggested a significant similarity by obtaining the estimated 95th percentile of the distribution of the estimator (ρ̂(95%)) at 0.0056 (p-value = 0.0026) and 0.0026 (p-value < 0.0001), respectively. In contrast, the ρ̂ was 0.036 (p-value = 1.00), while comparing Copaxone and the negative control, implying a lack of similarity. We further synthesized nine stable isotope-labeled peptides to validate the proposed amino acid sequences in the database, demonstrating the correctness in sequence identification. The quantitation variations in our analytical procedures were determined to be 6.8-7.7%. This approach was found to have a great potential for evaluating the similarity between generic NBCDs and listed reference drugs, as well as to monitor the lot-to-lot variation.

Extracorporeal shockwave therapy in the management of knee osteoarthritis: A systematic review of dose-response meta-analysis.

Introduction: The aim of the research was to conduct a systematic review of dose-response meta-analysis, examining the correlation between the energy of extracorporeal shockwave therapy (ESWT) and clinical outcomes for patients with knee osteoarthritis (OA). Methods: We conducted a systematic review of three online databases - PubMed, Embase, and Cochrane Library - to collect relevant articles from their inception to May 2023. We included the articles that investigated the efficacy of ESWT in treating knee OA and were designed using randomized controlled trials (RCTs). The main outcomes were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for primary outcomes and the Visual Analog Scale (VAS) for secondary outcomes. We conducted a dose-response meta-analysis to examine the correlation between the energy of ESWT and clinical outcomes. Results: Our study included a total of 7 RCTs (comprising 450 subjects) that met the inclusion criteria. We found a negative linear relationship between the doses of ESWT and WOMAC scores at the 1-week (p = 0.0398) and 4-week (p = 0.001) follow-up periods, but not at the 12-week follow-up period (p = 0.202). Furthermore, at the 4-week (p = 0.0477) and 12-week (p < 0.001) follow-up periods, a negative linear connection was found between the ESWT dose and VAS scores, but not at the 1-week follow-up period (p = 0.2268). Conclusions: Our results demonstrate a dose-response connection between the energy of ESWT and clinical outcomes. This suggests that using higher energy levels of ESWT to treat knee OA could lead to greater improvement in clinical outcomes compared to using lower energy levels.

A systematic review of the use of shockwave therapy for knee osteoarthritis.

Introduction: Previous studies assessed the effect of extracorporeal shockwave therapy (ESWT) for knee osteoarthritis (OA) among different situations. Thus, results from a meta-analysis regarding this topic may not be reliable due to heterogeneity. Methods: A systematic review was conducted on three internet databases, namely Cochrane Library, PubMed, and Embase, gathering pertinent papers from their establishment to March 2024. The search phrases were as follows: "shockwave" OR "shock wave" OR "extracorporeal shockwave" OR "Extracorporeal Shockwave Therapy [MeSH Term]" AND "knee" AND ("osteoarthritis" OR "arthritis" OR "arthritic" OR "osteoarthritis [MeSH term]"). Results: Twenty-four articles (n = 888) were included, with the resulting conclusions demonstrating that ESWT was effective for knee OA compared with sham ESWT; however, ESWT was not effective for patients with severe knee OA. Patients receiving higher energy or higher shock number had significant improvement than those receiving lower energy or less shock number, respectively. Adding ESWT in isokinetic muscular strengthening exercises (IMSE) was more effective than IMSE alone. The efficacy of ESWT was better than other therapies, including intravenously applied prostacyclin and bisphosphonate, corticosteroid injection, kinesiotherapy, hyaluronic acid injection, platelet-rich plasma injection, and physiotherapy. Conclusions: This review demonstrated that ESWT was effective for knee OA. Higher energy and more shock numbers could obtain better efficacy. ESWT could be used as a replacement for some other therapies.

Effective suppression of Ih and INa caused by capsazepine, known to be a blocker of TRPV1 receptor.

A synthetic inhibitor of capsaicin-induced TRPV1 channel activation is called capsazepine (CPZ). In this study, we aimed to explore the effects of CPZ on hyperpolarization-activated cationic current (Ih) and voltage-gated Na + current (INa) in pituitary tumor (GH3) cells. Through patch-clamp recordings, we found that CPZ concentration-dependently inhibited Ih amplitude and slowed its activation time course. The IC50 and KD values were 3.1 and 3.16 µM, respectively. CPZ also shifted the steady-state activation curve of Ih towards a more hyperpolarized potential. However, there was no change in the gating charge of the curve. A modified Markovian model predicted the CPZ-induced decrease in the voltage-dependent hysteresis of Ih. CPZ suppressed INa in GH3 cells, without altering its activation or inactivation time course. Additionally, exposure to CPZ reduced spontaneous firing. These findings suggest that CPZ's inhibitory effects on Ih and INa are direct and not dependent on vanilloid receptor binding. This could provide light on an unidentified ionic mechanism influencing the membrane excitability of neurons and endocrine or neuroendocrine cells in vivo.

Efficacy of turmeric in the treatment of oral mucositis in patients with head and neck cancer after radiotherapy or chemoradiotherapy: a systematic review and meta-analysis.

Background: Oral mucositis is a major complication for head and neck cancer (HNC) patients after radiotherapy or chemotherapy. A meta-analysis was performed to assess the efficacy of turmeric in the treatment of oral mucositis in HNC patients. Methods: Randomized controlled trials investigating our topic were included in the meta-analysis. The clinical outcomes considered were the severity of oral mucositis, pain level, and weight loss. Results: A total of eight articles that met our inclusion criteria were included in our meta-analysis. At the 3-week follow-up visit, the turmeric group showed significantly lower grades of oral mucositis compared to the control group (p = 0.03). When compared to the placebo group, a significant difference in the degree of oral mucositis was observed at the 4-(p = 0.03) and 6-week (p < 0.00001) follow-up visits. No significant difference in pain levels was observed between the turmeric and control groups at any of the follow-up visits. However, a significant improvement in pain levels for the turmeric group when compared with the placebo group was observed only at the 6-week follow-up visit (p = 0.006). Interestingly, a significant improvement in pain levels was observed for the turmeric group at the 2-, 4-, 5-, and 6-week follow-up visits (p < 0.05) when compared to the non-placebo group. The turmeric group showed less weight loss than the control group at the final follow-up visit (p = 0.03). conclusion: Our meta-analysis showed that using turmeric may be effective in improving both the severity of oral mucositis and pain levels in HNC patients who have received radiotherapy or radiochemotherapy. In addition, the turmeric group experienced less weight loss.

Effects of vitamin D in pregnancy on maternal and offspring health-related outcomes: An umbrella review of systematic review and meta-analyses.

BACKGROUND: Vitamin D deficiency has been linked with several adverse maternal and fetal outcomes. OBJECTIVE: To summarize systematic reviews and meta-analyses evaluating the effects of vitamin D deficiency and of vitamin D supplementation in pregnancy on maternal and offspring health-related outcomes. METHODS: Prior to conducting this umbrella review, we registered the protocol in PROSPERO (CRD42022368003). We conducted searches in PubMed, Embase, and Cochrane Library for systematic reviews and meta-analyses on vitamin D in pregnancy, from database inception to October 2, 2023. All outcomes related to vitamin D in pregnancy obtained from the systematic reviews and meta-analyses were extracted. DATA EXTRACTION: Two reviewers independently chose studies and collected information on health outcomes. The quality of the included articles' methodology was assessed using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews-2). RESULTS: We identified 16 eligible systematic reviews and meta-analyses, which included 250,569 women. Our results demonstrated that vitamin D deficiency in pregnancy is associated with increased risk of preterm birth, small-for gestational age/low birth weight infants, recurrent miscarriage, bacterial vaginosis and gestational diabetes mellitus. Vitamin D supplementation in pregnancy increases birth weight, and reduces the risk of maternal pre-eclampsia, miscarriage, and vitamin D deficiency, fetal or neonatal mortality, as well as attention-deficit hyperactivity disorder, and autism spectrum disorder in childhood. In women with gestational diabetes mellitus, vitamin D supplementation in pregnancy can reduce the risk of maternal hyperbilirubinemia, polyhydramnios, macrosomia, fetal distress, and neonatal hospitalization. CONCLUSION: Due to the association with adverse maternal and offspring health outcomes, we recommend the vitamin D status in pregnancy should be monitored, particularly in women at high risk of vitamin D deficiency. It is suggested that pregnant women take a dose of >400 IU/day of vitamin D supplementation during pregnancy to prevent certain adverse outcomes.

The Effect of Job Satisfaction on Psychological Well-Being for Taiwanese Home-Care Workers, Mediated by Emotional Labor.

The objective of this study was to investigate the effect of job satisfaction on psychological well-being through emotional labor for Taiwanese home-care workers. A total of 316 home-care workers who worked in Chiayi, Taiwan, were recruited in this study. Most of the participants were Taiwanese (96.5%). The mean age of the participants was 42.05 ± 12.15 years, and the participants were predominantly female (80%). The mean work experience was 5.64 ± 5.13 years. Job satisfaction, emotional labor, and psychological well-being were measured. Partial least squares structural equation modeling was used to examine the direct and indirect effects on job satisfaction, emotional labor, and psychological well-being. The results demonstrated that the internal factors of job satisfaction had indirect effects on psychological well-being through the mediating effects of surface acting and deep acting. However, it was also observed that the external factors of job satisfaction had indirect effects on psychological well-being through the mediating effect of surface acting but not deep acting. The model explained 57.6% of the variance in psychological well-being. The internal factors of job satisfaction are more important than the external factors affecting psychological well-being through the mediating effect of deep acting. Based on our results, we recommend enhancing the deep acting of emotional labor to improve the psychological well-being of Taiwanese home-care workers.

Dose-response technique combined with stable isotope tracing for drug metabolite profiling by using high-resolution mass spectrometry.

Background: Mass spectrometry metabolomics-based data-processing approaches have been developed for drug metabolite profiling. However, existing approaches cannot be used to comprehensively identify drug metabolites with high efficacy. Methods: Herein, we propose a two-stage data-processing approach for effective and comprehensive drug metabolite identification. The approach combines dose-response experiments with stable isotope tracing (SIT). Rosiglitazone (ROS), commonly used to treat type 2 diabetes, was employed as a model drug. Results: In the first stage of data processing, 1,071 features exhibited a dose-response relationship among 22,597 features investigated. In the second stage, these 1,071 features were screened for isotope pairs, and 200 features with isotope pairs were identified. In time-course experiments, a large proportion of the identified features (69.5%: 137 out of 200 features) were confirmed to be possible ROS metabolites. We compared the validated features identified using our approach with those identified using a previously reported approach [the mass defect filter (MDF) combined with SIT] and discovered that most of the validated features (37 out of 42) identified using the MDF-SIT combination were also successfully identified using our approach. Of the 143 validated features identified by both approaches, 74 had a proposed structure of an ROS-structure-related metabolite; the other 34 features that contained a specific fragment of ROS metabolites were considered possible ROS metabolites. Interestingly, numerous ROS-structure-related metabolites were identified in this study, most of which were novel. Conclusion: The results reveal that the proposed approach can effectively and comprehensively identify ROS metabolites.

Characterization of Stimulatory Action on Voltage-Gated Na+ Currents Caused by Omecamtiv Mecarbil, Known to Be a Myosin Activator.

Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. The objective of this study was to investigate the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells. In GH3 cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient (INa(T)) and late components (INa(L)) of the voltage-gated Na+ current (INa) with different potencies in GH3 cells. The EC50 value required to observe the stimulatory effect of this compound on INa(T) or INa(L) in GH3 cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of INa(T). However, the steady-state inactivation curve of the current was observed to shift towards a depolarized potential of approximately 11 mV, with no changes in the slope factor of the curve. The addition of OM resulted in an increase in the decaying time constant during the cumulative inhibition of INa(T) in response to pulse-train depolarizing stimuli. Furthermore, the presence of OM led to a shortening of the recovery time constant in the slow inactivation of INa(T). Adding OM also resulted in an augmentation of the strength of the window Na+ current, which was evoked by a short ascending ramp voltage. However, the OM exposure had little to no effect on the magnitude of L-type Ca2+ currents in GH3 cells. On the other hand, the delayed-rectifier K+ currents in GH3 cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of INa(T) or INa(L) upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNaV1.7 channels. Overall, the direct stimulation of INa(T) and INa(L) by OM is assumed to not be mediated by an interaction with myosin, and this has potential implications for its pharmacological or therapeutic actions occurring in vivo.

Comparing the effects of water temperature and additives in glucose solution on pregnant women's taste, side effects, and glycemic levels during an oral glucose tolerance test: a randomized controlled trial.

BACKGROUND: The oral glucose tolerance test is a common method of diagnosing gestational diabetes mellitus. This test causes several unpleasant side effects such as nausea, vomiting, abdominal bloating, and headache. OBJECTIVE: This study aimed to assess the effect of liquid temperature and additives on pregnant women's taste perception, side effects, and glycemic levels in an oral glucose tolerance test. STUDY DESIGN: This study was a single-center, randomized, and multi- and open-arm clinical trial. A total of 399 participants receiving the 75-g oral glucose tolerance test for gestational diabetes mellitus diagnosis were included. Solutions for use in the 75-g oral glucose tolerance test were prepared in 8 formulas, with the participants randomly assigned to 1 of the 8 groups: room-temperature water, hot water, cold water, hot water with tea bag, room-temperature water with tea bag, cold water with tea bag, room-temperature soda water, and cold soda water. The main study outcomes were glycemic levels, satisfaction, perceived taste, side effects, and gestational diabetes mellitus. Glycemic levels were measured when fasted and at 1 hour and 2 hours after glucose administration. Satisfaction, taste perception, and side effects were evaluated immediately after the oral glucose tolerance test, and gestational diabetes mellitus was determined on the basis of glycemic levels. RESULTS: The cold soda water solution led to a significantly higher glycemic level at 1 hour after glucose intake compared with room-temperature soda water solution (P=.009). Glucose formula was found to not significantly affect gestational diabetes mellitus incidence (P>.05) or the participants' satisfaction, vomiting, headache, or abdominal bloating (P>.05). However, the formula did significantly affect perceived taste (P=.027) and the degree of nausea (P=.014). CONCLUSION: Several glucose solutions, such as cold glucose solution and any-temperature glucose solution containing a tea bag, led to slightly higher taste scores and a lower degree of nausea compared with the room-temperature water-based glucose solution. However, soda water was found to affect the glycemic level at 1 hour after glucose intake, and is not suggested for use for gestational diabetes mellitus diagnosis.