Genetically predicted causal effects of gut microbiota on spinal pain: a two-sample Mendelian randomization analysis.

Background: Observational studies have hinted at a correlation between the gut microbiota and spinal pain (SP). However, the impact of the gut microbiota on SP remains inconclusive. Methods: In this study, we employed a two-sample Mendelian randomization (MR) analysis to explore the causal relationship between the gut microbiota and SP, encompassing neck pain (NP), thoracic spine pain (TSP), low back pain (LBP), and back pain (BP). The compiled gut microbiota data originated from a genome-wide association study (GWAS) conducted by the MiBioGen consortium (n = 18,340). Summary data for NP were sourced from the UK Biobank, TSP from the FinnGen Biobank, and LBP from both the UK Biobank and FinnGen Biobank. Summary data for BP were obtained from the UK Biobank. The primary analytical approach for assessing causal relationships was the Inverse Variance Weighted (IVW) method, supplemented by various sensitivity analyses to ensure result robustness. Results: The IVW analysis unveiled 37 bacterial genera with a potential causal relationship to SP. After Benjamini-Hochberg corrected test, four bacterial genera emerged with a strong causal relationship to SP. Specifically, Oxalobacter (OR: 1.143, 95% CI 1.061-1.232, P = 0.0004) and Tyzzerella 3 (OR: 1.145, 95% CI 1.059-1.238, P = 0.0007) were identified as risk factors for LBP, while Ruminococcaceae UCG011 (OR: 0.859, 95% CI 0.791-0.932, P = 0.0003) was marked as a protective factor for LBP, and Olsenella (OR: 0.893, 95% CI 0.839-0.951, P = 0.0004) was recognized as a protective factor for low back pain or/and sciatica. No significant heterogeneity or horizontal pleiotropy was observed through alternative testing methods. Conclusion: This study establishes a causal relationship between the gut microbiota and SP, shedding light on the "gut-spine" axis. These findings offer novel perspectives for understanding the etiology of SP and provide a theoretical foundation for potential interventions targeting the gut microbiota to prevent and treat SP.

Gene association analysis to determine the causal relationship between immune cells and juvenile idiopathic arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a type of chronic childhood arthritis with complex pathogenesis. Immunological studies have shown that JIA is an acquired self-inflammatory disease, involving a variety of immune cells, and it is also affected by genetic and environmental susceptibility. However, the precise causative relationship between the phenotype of immune cells and JIA remains unclear to date. The objective of our study is to approach this inquiry from a genetic perspective, employing a method of genetic association analysis to ascertain the causal relationship between immune phenotypes and the onset of JIA. METHODS: In this study, a two-sample Mendelian randomization (MR) analysis was used to select single nucleotide polymorphisms (SNPs) significantly associated with immune cells as instrumental variables to analyze the bidirectional causal relationship between 731 immune cells and JIA. There were four types of immune features (median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC), and morphological parameters (MP)). Finally, the heterogeneity and horizontal reproducibility of the results were verified by sensitivity analysis, which ensured more robust results. RESULTS: We found that CD3 on CM CD8br was causally associated with JIA at the level of 0.05 significant difference (95% CI = 0.630 ~ 0.847, P = 3.33 × 10-5, PFDR = 0.024). At the significance level of 0.20, two immunophenotypes were causally associated with JIA, namely: HLA DR on CD14+ CD16- monocyte (95% CI = 0.633 ~ 0.884, P = 6.83 × 10-4, PFDR = 0.16) and HLA DR on CD14+ monocyte (95% CI = 0.627 ~ 0.882, P = 6.9 × 10-4, PFDR = 0.16). CONCLUSION: Our study assessed the causal effect of immune cells on JIA from a genetic perspective. These findings emphasize the complex and important role of immune cells in the pathogenesis of JIA and lay a foundation for further study of the pathogenesis of JIA.

Manual Therapy for a Chronic Non-Specific Low Back Pain Rat Model.

Chronic low back pain (CLBP) is a highly prevalent condition worldwide and a major cause of disability. The majority of patients with CLBP are diagnosed with chronic non-specific low back pain (CNLBP) due to an unknown pathological cause. Manual therapy (MT) is an integral aspect of traditional Chinese medicine and is recognized as Tuina in China. It involves techniques like bone-setting and muscle relaxation manipulation. Despite its clinical efficacy in treating CNLBP, the underlying mechanisms of MT remain unclear. In animal experiments aimed at investigating these mechanisms, one of the main challenges is achieving normative MT on CNLBP model rats. Improving the stability of finger strength is a key issue in MT. To address this technical limitation, a standardized procedure for MT on CNLBP model rats is presented in this study. This procedure significantly enhances the stability of MT with the hands and alleviates common problems associated with immobilizing rats during MT. The findings of this study are of reference value for future experimental investigations of MT.

Interphase Modulated Early-Stage Zn Electrodeposition Mechanism.

Zn electrodeposition mechanism is a cornerstone of dendritic issue exploration in Zn-ion battery. Investigation of the inherent early-stage Zn plating kinetics and its dependence on the reactivity of anode-electrolyte interphase is crucial. Herein, the kinetic evolution of Zn plating on three characteristic substrates is quantified: fresh Zn, commercial Zn foil, and Zn foil with spontaneously generated solid-electrolyte interphase (SEI). Using scanning electrochemical microscopy analysis, the original interphase regulation of Zn deposit orientation and the competitive reaction between Zn deposition and SEI passivation are studied in situ. Furthermore, the SEI layer can suppress the dendrite growth at initial state by guiding the horizontal alignment of Zn flakes and promote Zn plating process. This approach provided a feasible consideration into interphase engineering of various metal anodes.

Lever positioning manipulation alters real-time brain activity in patients with lumbar disc herniation: An amplitude of low-frequency fluctuation and regional homogeneity study.

INTRODUCTION: Lumbar disk herniation (LDH) is the preeminent disease of lever positioning manipulation (LPM), a complex disorder involving alterations in brain function. Resting-state functional magnetic resonance imaging (rs-fMRI) has the advantages of non-trauma, zero radiation, and high spatial resolution, which has become an effective means to study brain science in contemporary physical therapy. Furthermore, it can better elucidate the response characteristics of the brain region of LPM intervention in LDH. We utilized two data analysis methods, the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) of rs-fMRI, to assess the effects of LPM on real-time brain activity in patients with LDH. METHODS: Patients with LDH (Group 1, n = 21) and age-, gender- and education-matched healthy controls without LDH (Group 2, n = 21) were prospectively enrolled. Brain fMRI was performed for Group 1 at two-time points (TPs): before LPM (TP1) and after one LPM session (TP2). The healthy controls (Group 2) did not receive LPM and underwent only one fMRI scan. Participants in Group 1 completed clinical questionnaires assessing pain and functional disorders using a Visual Analog Scale and the Japanese Orthopaedic Association (JOA), respectively. Furthermore, we employed MNL90 (Montreal Neurological Institute) as a brain-specific template. RESULTS: Compared to the healthy controls (Group 2), the patients with LDH (Group 1) had significant variation in ALFF and ReHo values in brain activity. After the LPM session (TP2), Group 1 at TP1 also showed significant variation in ALFF and ReHo values in brain activity. In addition, the latter (TP2 vs TP1) showed more significant changes in brain regions than the former (Group 1 vs Group 2). The ALFF values were increased in the Frontal_Mid_R and decreased in the Precentral_L in Group 1 at TP2 compared with TP1. The Reho values were increased in the Frontal_Mid_R and decreased in the Precentral_L in Group 1 at TP2 compared with TP1. The ALFF values were increased in the Precuneus_R and decreased in the Frontal_Mid_Orb_L in Group 1 compared with Group 2. Only three brain areas with significant activity in Group 1 compared with Group 2: Frontal_Mid_Orb_L, Frontal_Sup_Orb_L, and Frontal_Mid_R. ALFF value in the Frontal_Mid_R at TP2 correlated positively with the change rates of JOA scores between TP1 and TP2 (P = 0.04, r = 0.319, R2 = 0.102). DISCUSSION: Patients with LDH showed abnormal brain ALFF and ReHo values, which were altered after LPM. The default mode network, prefrontal cortex, and primary somatosensory cortex regions could predict real-time brain activity for sensory and emotional pain management in patients with LDH after LPM.

Bibliometric Analysis of Functional Magnetic Resonance Imaging Studies on Manual Therapy Analgesia from 2002-2022.

Background: Research on the brain mechanisms underlying manual therapy (MT)-induced analgesia has been conducted worldwide. However, no bibliometric analysis has been performed on functional magnetic resonance imaging (fMRI) studies of MT analgesia. To provide a theoretical foundation for the practical application of MT analgesia, this study examined the current incarnation, hotspots, and frontiers of fMRI-based MT analgesia research over the previous 20 years. Methods: All publications were obtained from the Science Citation Index-Expanded (SCI-E) of Web of Science Core Collection (WOSCC). We used CiteSpace 6.1.R3 to analyze publications, authors, cited authors, countries, institutions, cited journals, references, and keywords. We also evaluated keyword co-occurrences and timelines, and citation bursts. The search was conducted from 2002-2022 and was completed within one day on October 7, 2022. Results: In total, 261 articles were retrieved. The total number of annual publications showed a fluctuating but overall increasing trend. Author B. Humphreys had the highest number of publications (eight articles) and J. E. Bialosky had the highest centrality (0.45). The United States of America (USA) was the country with the most publications (84 articles), accounting for 32.18% of all publications. Output institutions were mainly the University of Zurich, University of Switzerland, and the National University of Health Sciences of the USA. The Spine (118) and the Journal of Manipulative and Physiological Therapeutics (80) were most frequently cited. The four hot topics in fMRI studies on MT analgesia were "low back pain", "magnetic resonance imaging", "spinal manipulation", and "manual therapy." The frontier topics were "clinical impacts of pain disorders" and "cutting-edge technical capabilities offered by magnetic resonance imaging". Conclusion: fMRI studies of MT analgesia have potential applications. fMRI studies of MT analgesia have linked several brain areas, with the default mode network (DMN) garnering the most attention. Future research should include international collaboration and RCTs on this topic.

A systematic review and meta-analysis of randomized controlled trials of manipulative therapy for patients with chronic neck pain.

BACKGROUND: An increasing number of people suffer from chronic neck pain due to increased telecommuting. Manual therapy is considered a safe and less painful method and has been increasingly used to alleviate chronic neck pain. However, there is controversy about the effectiveness of manipulation therapy on chronic neck pain. Therefore, this systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to determine the effectiveness of manipulative therapy for chronic neck pain. METHODS: A search of the literature was conducted on seven databases (PubMed, Cochrane Center Register of Controlled Trials, Embase, Medline, CNKI, WanFang, and SinoMed) from the establishment of the databases to May 2022. This study included RCTs on chronic neck pain managed with manipulative therapy compared with sham, exercise, and other physical therapies. The retrieved records were independently reviewed by two researchers. Further, the methodological quality was evaluated using the PEDro scale. All statistical analyses were performed using RevMan V.5.3 software. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment was used to evaluate the quality of the study results. RESULTS: Seventeen RCTs, including 1190 participants, were included in this meta-analysis. Manipulative therapy showed better results regarding pain intensity and neck disability than the control group. Manipulative therapy was shown to relieve pain intensity (SMD = -0.83; 95% confidence interval [CI] = [-1.04 to -0.62]; p < 0.0001) and neck disability (MD = -3.65; 95% CI = [-5.67 to - 1.62]; p = 0.004). However, the studies had high heterogeneity, which could be explained by the type and control interventions. In addition, there were no significant differences in adverse events between the intervention and the control groups. CONCLUSIONS: Manipulative therapy reduces the degree of chronic neck pain and neck disabilities.

Efficacy of traditional Chinese exercises in patients with post-COVID-19 chronic fatigue syndrome: A protocol for systematic review and meta-analysis.

BACKGROUND: Some patients develop long-term symptoms after Corona virus disease 2019 (COVID-19), and chronic fatigue syndrome (CFS) is one of the main symptoms. CFS is characterized by fatigue lasting for more than 6 months accompanied by sleep disorders, anxiety, and depression, which causes a certain degree of harm to both physiological and psychological aspects of the individual. Traditional Chinese exercises (TCEs) are an ancient Chinese therapy and has recently been reported to be effective for CFS. Therefore, we will conduct a systematic review and meta-analysis aiming to accurately evaluate the efficacy of TCEs on post-COVID-19 CFS and provide an alternative treatment for post-COVID-19 CFS. METHODS: Seven databases (PubMed, Ovid Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), and Wanfang) will be searched from establishment to August 2022, and we will only include randomized controlled trials of TCEs for post-COVID-19 CFS. Two reviews will independently include the research according to the inclusion and exclusion criteria. Review Manager 5.2 software will be used to analyze the accepted literature, and the relative risk ratio (RR) and 95% confidence interval (CI) will be used as effect indicators for the outcome indicator dichotomous variables. For continuous variables, weighted mean difference (MD) and 95% CI will be used as effect indicators. The heterogeneity test will be assessed using the I2 statistic and Q statistic. The PEDro scale was used to evaluate the methodological quality of the included studies. Subgroup analysis was performed according to different TCEs, age, gender, and duration of CFS. RESULTS: This systematic review and meta-analysis will evaluate the efficacy of TCEs in post-COVID-19 CFS. CONCLUSION: The results of this study will provide reliable evidence for the effects of TCEs for post-COVID-19 CFS on patients' fatigue, anxiety, depression, sleep, and quality of life.

Effectiveness and safety of acupuncture and moxibustion for chronic prostatitis: A protocol for an overview of systematic reviews and meta-analysis.

BACKGROUND: Chronic prostatitis (CP) refers to a disease characterized by local pain and discomfort, urination discomfort, and quality of life. Acupuncture (ACU) and moxibustion are widely used in the treatment of CP, and the curative effect is satisfactory. Several systematic reviews (SRs) and meta-analyzes have reported the effectiveness of ACU and moxibustion in treating patients with CP. However, the evidence is not systematically integrated. This overview aims to integrate and evaluate the reliability of these SRs and the evidence generated from the ACU and moxibustion for CP meta-analysis. METHODS: We will make a comprehensive retrieval in seven databases as following: Embase, Cochrane Library, Pubmed, Chinese databases SinoMed (previously called the Chinese Biomedical Database), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wanfang Data (WF). The time is limited from the construction of the library to May 2021. We will use the Assessment of Multiple Systematic Reviews-2 (AMSTAR-2) tool to evaluate methodological quality. Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols (PRISMA-P) will be used in the report checklist to assess the quality of reports in the study. The GRADE will be used to evaluate the included SRs and meta-analysis. Our reviewers will conduct SRs, qualification evaluation, data extraction, methodological quality and evidence quality screening in pairs. The outcomes of interest include: NIH-Chronic Prostatitis Symptom Index (NIH-CPSI), effective rate, other CP symptom scales, EPS-WBC, and adverse events. Evidence will be combined based on patient subgroups and results where appropriate. RESULTS: The results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: INPLASY202150018. CONCLUSION: This overview will provide comprehensive evidence of ACU and moxibustion for patients with CP.

Effect of traditional Chinese exercise combined with massage on pain and disability in patients with lumbar disc herniation: A multi-center, randomized, controlled, assessor-blinded clinical trial.

Background: Herniation of the nucleus pulposus caused by disc degeneration and other reasons can cause low back pain and disability. In China, traditional Chinese exercises (TCEs) and traditional Chinese massage (TCM) are widely used to improve symptoms of pain and disability in patients with lumbar disc herniation (LDH). The safety and efficacy of combination therapy have not been studied. Objectives: To assess the effect of traditional Chinese exercise combined with massage vs. traditional Chinese massage alone on pain, disability, lumbar mobility and gait performance in patients with LDH. Methods: Multi-center, randomized clinical trial conducted at 4 hospitals in China and enrolling 272 patients with LDH. Participants were randomly assigned to TCEs plus TCM group or TCM alone group. The combined therapy group received 18 Tai Chi training sessions (30-min sessions 3 times a week) and regular TCM treatments over 6 weeks. The control group received TCM therapy alone and was instructed to maintain their usual daily physical activity. Outcome variables measured included Visual Analog Scale (VAS), Short Form of McGill Pain Questionnaire (SF-MPQ), Oswestry Disability Index (ODI), lumbar spine range of motion (ROM) and gait performance. Results: Among the 272 randomized participants, 259 completed the study. The mean VAS score was 51.77 mm at baseline in the TCEs plus TCM group, and 50.93 mm for the TCM alone group. The reduction in the VAS score at week 6 was greater in the TC group than in the TCM group with a mean difference of 4.05 (95% CI, 2.15-5.95; P < 0.001), and the ODI score with between-group differences of 3.57 points (95% CI, 2.84-4.30 points; P < 0.001). Similar significantly different results were observed in SF-MPQ, walking speed, cadence, and lumbar ROM. No serious adverse events were reported throughout the study period. Conclusion: Compared with TCM alone, TCEs combined with TCM treatment performed better in reducing pain and improving disability. The combination therapy could be considered a valuable treatment option for LDH patients, with potential therapeutic utility for middle-aged and elderly patients with LDH.

Transcriptome profiling of microRNAs reveals potential mechanisms of manual therapy alleviating neuropathic pain through microRNA-547-3p-mediated Map4k4/NF-κb signaling pathway.

BACKGROUND: Local neuroinflammation secondary to spinal nerve compression in lumbar disk herniation (LDH) is a key driver contributing to neuropathic pain. Manual therapy (MT), a widely used nonsurgical therapy, can relieve LDH-mediated pain by reducing inflammation. MT has attracted extensive attention; however, its mechanism remains poorly understood. MicroRNAs (miRNAs) are important regulators of pain signaling transduction, but are rarely reported in the chronic compression of dorsal root ganglia (CCD) model, and further investigation is needed to decipher whether they mediate anti-inflammatory and analgesic effects of MT. METHODS: We used a combination of in vivo behavioral and molecular techniques to study MT intervention mechanisms. Neuropathic pain was induced in a CCD rat model and MT intervention was performed according to standard procedures. Enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory cytokine levels in dorsal root ganglia (DRG). Small RNA sequencing, immunofluorescence, Western blot, and qRT-PCR were performed to screen miRNAs and their target genes and determine core factors in the pathway possibly regulated by miRNA-mediated target gene in DRG of MT-treated CCD rats. RESULTS: Compared with naive rats, small RNA sequencing detected 22 differentially expressed miRNAs in DRG of CCD rats, and compared with CCD rats, MT-treated rats presented 19 differentially expressed miRNAs, which were functionally associated with nerve injury and inflammation. Among these, miR-547-3p was screened as a key miRNA mediating neuroinflammation and participating in neuropathic pain. We confirmed in vitro that its function is achieved by directly regulating its target gene Map4k4. Intrathecal injection of miR-547-3p agomir or MT intervention significantly reduced Map4k4 expression and the expression and phosphorylation of IκBα and p65 in the NF-κB pathway, thus reducing the inflammatory cytokine levels and exerting an analgesic effect, whereas intrathecal injection of miR-547-3p antagomir led to opposite effects. CONCLUSIONS: In rats, CCD-induced neuropathic pain leads to variation in miRNA expression in DRG, and MT can intervene the transcription and translation of inflammation-related genes through miRNAs to improve neuroinflammation and alleviate neuropathic pain. MiR-547-3p may be a key target of MT for anti-inflammatory and analgesia effects, which is achieved by mediating the Map4k4/NF-κB pathway to regulate downstream inflammatory cytokines.

Clinical Evidence for the Effects of Manual Therapy on Cancer Pain: A Systematic Review and Meta-Analysis.

OBJECTIVE: This meta-analysis aimed to evaluate the effects of manual therapy (MT) on cancer pain, so as to provide clinical evidence for application. METHODS: Five English and Chinese databases were searched until February 29, 2020, for randomized controlled trials (RCTs) of MT for cancer pain. Articles published in the English or Chinese language were included. Two authors independently reviewed all articles and extracted the data, and any disagreements in the above process were discussed with other reviewers until the authors reached consensus. Review Manager 5.3 was used to calculate the effect size and 95% confidence intervals. This review was registered in PROSPERO, number CRD42020172053. RESULTS: The intensity of cancer pain is our primary outcome measure, and compared with standard care, MT can significantly relieve the pain of patients with cancer (SMD, 0.63; 95% CI [0.18, 1.08]; P=0.006 < 0.01); the effects of MT plus active activity were significantly different from AT alone (SMD, 0.79; 95% CI [0.28, 1.30]; P=0.002 < 0.01); there was no statistical difference in the efficacy of MT and AT alone (SMD, -0.24; 95% CI [-1.09, 0.62]; P=0.53 > 0.05). In other related symptoms, the above evidence cannot support that MT had a good effect on fatigue (SMD, 0.77; 95% CI [-0.09, 1.63]; P=0.08 > 0.05), nausea (SMD, 0.24; 95% CI [-0.00, 0.48]; P=0.05), anxiety (SMD, 0.76; 95 % CI [-0.32, 1.84]; P=0.17 > 0.05), and depression (SMD, 0.67; 95 % CI [-0.28, 1.62]; P=0.17 > 0.05); however, MT intervention can improve physical function (n = 271; SMD, 0.35; 95 % CI [-0.04, 0.74]; P=0.04 < 0.05) and global well-being (SMD, 0.50; 95 % CI [0.02, 0.98]; P=0.04 < 0.05). In addition, MT had a significant effect on pain relief (SMD, 0.52; 95% CI [0.03, 1.01]; P=0.04 < 0.05) and improvement of physical function (SMD, 0.28; 95% CI [0.02, 0.53]; P=0.03 < 0.05) even after a period of time after treatment. CONCLUSION: MT was an effective intervention, which may have immediate effect on cancer pain and may improve physical function and global well-being. In the view of follow-up effects, MT had good effects for the reduction of pain and the recovery of physical function. However, because of limitations, the seemingly promising results should be interpreted with caution.

Efficacy of Liu-zi-jue in Patients with 2019 Novel Coronavirus Pneumonia (COVID-19): structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: Efficacy of conventional treatment plus the complementary therapy Liu-zi-jue (a mind-body exercise) to treat patients with mild COVID-19. TRIAL DESIGN: The study is a single-center 2 arm, randomized controlled trial with parallel-group design.

Efficacy of Tuina in patients with chronic low back pain: study protocol for a randomized controlled trial.

BACKGROUND: Low back pain is a common reason for medical care and carries a heavy social burden. The efficacy of Tuina or health care education for low back pain has been evaluated in previous systematic reviews. However, there is no evidence to support the superiority of one form of treatment over another. The aim of this study is to compare the efficacy of Tuina with health care education in the management of low back pain. METHODS/DESIGN: This study is a randomized controlled trial with parallel-group design including two groups: a Tuina group and a health care education group. A total of 160 eligible participants will be randomly assigned to the groups in a 1:1 ratio. The interventions of both groups will last for 20 min and be carried out twice each week for a period of 12 weeks. The primary outcome is the Oswestry Disability Index. The secondary outcomes include a visual analogue scale and the 36-item Short Form Health Survey. They will be assessed at baseline, at the end of the intervention every month, and during 6 months and 9 months of follow-up by repeated measures analysis of variance. The significance level is 5%. The safety of Tuina and health care education will be evaluated after each treatment session. This study will focus on the value of Tuina and health care education for low back pain and will highlight any differences in the efficacy of the treatments. DISCUSSION: This study will evaluate the efficacy and safety of Tuina intervention for low back pain, which could provide reliable evidence for clinical decision making for patients with low back pain. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900022656. Registered on 23 April 2019.

Efficacy of tuina in patients with chronic neck pain: study protocol for a randomized controlled trial.

BACKGROUND: Chronic neck pain (CNP) is a common and disabling musculoskeletal disorder in developing and developed countries. Previous studies have shown that tuina and traditional Chinese massage are effective treatments for patients with CNP. However, there is little evidence to support the use of one intervention over the other. The aim of this study is to compare the effects of tuina and traditional Chinese massage in the treatment of pain and disability in patients with CNP. METHODS/DESIGN: This is a multicenter, assessor- and analyst-blinded, randomized controlled trial with two parallel arms: a tuina group and a traditional Chinese massage group. A total of 356 eligible CNP patients will be randomly assigned to the groups in a 1:1 ratio. The intervention in the tuina group includes both structural and relaxation massage, while the traditional Chinese massage group will receive relaxation massage only. The interventions for both groups will last for 15 min and will be carried out three times a week for a period of 4 weeks. The primary outcome will be changes in the Northwick Park Neck Pain Questionnaire. Secondary outcomes will be measured by a visual analogue scale (VAS), the Neck Disability Index (NDI), and the 36-item Short-Form Health Survey (SF-36). The data will be analyzed at the baseline, at the end of the intervention, and during the 3 months of follow-up by repeated measures analysis of variance. The significance level is 5%. The safety of tuina and traditional Chinese massage will be evaluated after each treatment session. The results of this trial will help clarify the value of tuina and traditional Chinese massage as treatments for CNP and will highlight any differences in the efficacy of the treatments. DISCUSSION: The purpose of this trial is to determine whether tuina is more effective than traditional Chinese massage in adults with CNP. This trial will, therefore, contribute to providing a solid foundation for clinical treatment of CNP, as well as future research in massage therapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-INR-17013763 . Registered 8 December 2017.

Mitochondria are transported along microtubules in membrane nanotubes to rescue distressed cardiomyocytes from apoptosis.

Membrane nanotubes (MNTs) act as "highways" between cells to facilitate the transfer of multiple signals and play an important role in many diseases. Our previous work reported on the transfer of mitochondria via MNTs between cardiomyocytes (CMs) and cardiac myofibroblasts (MFs); however, the elucidation of the underlying mechanism and pathophysiological significance of this transfer requires additional study. In this study, we determined that the mean movement velocity of mitochondria in MNTs between CMs and MFs was approximately 17.5 ± 2.1 nm/s. Meanwhile, treatment with microtubule polymerisation inhibitors nocodazole or colcemid in cell culture decreased mitochondrial velocity, and knockdown of the microtubule motor protein kinesin family member 5B (KIF5B) led to a similar effect, indicating that mitochondrial movement was dependent on microtubules and the motor protein KIF5B. Furthermore, we showed that hypoxia/reoxygenation-induced CM apoptosis was attenuated by coculture with intact or hypoxia/reoxygenation-treated MFs, which transferred mitochondria to CMs. This rescue was prevented either by separating the cells using Transwell culture or by impairing mitochondrial transfer with nocodazole or colcemid treatment. In conclusion, as a novel means of intercellular communication, MNTs rescue distressed CMs from apoptosis by transporting mitochondria along microtubules via KIF5B.

Downregulation of ß-Adrenoceptors in Isoproterenol-Induced Cardiac Remodeling through HuR.

ß-adrenergic receptors (ß-ARs) play an important role in cardiac remodeling, which is the key pathological process in various heart diseases and leads to heart failure. However, the regulation of ß-AR expression in remodeling hearts is still unclear. This study aims to clarify the possible mechanisms underlying the regulation of ß1- and ß2-AR expression in cardiac remodeling. The rat model of cardiac remodeling was established by subcutaneous injection of isoproterenol(ISO) at the dose of 0.25 mg·kg(-1)·d(-1) for 7 days. We found that the expression of ß1- and ß2-ARs decreased in the remodeling heart. The mechanisms may include the inhibition of DNA transcription and the increase of mRNA degradation. cAMP-response element binding protein(CREB) is a well-known transcription factor of ß-AR. However, the expression and activation of CREB was not changed in the remodeling heart. Further, human Antigen-R (HuR), a RNA binding protein, which binds to the 3'-untranslated region of the ß-AR mRNA and promotes RNA degradation, was increased in the remodeling model. And in vitro, HuR deficiency reversed the reduction of ß-AR mRNA induced by ISO. Therefore, the present findings indicate that HuR, but not CREB, is responsible for the reduction of ß-AR expression in ISO induced cardiac remodeling.

Internalization of the TGF-ß type I receptor into caveolin-1 and EEA1 double-positive early endosomes.

Endocytosis and intracellular sorting of transforming growth factor-ß (TGF-ß) receptors play an important regulatory role in TGF-ß signaling. Two major endocytic pathways, clathrin- and caveolae-mediated endocytosis, have been reported to independently mediate the internalization of TGF-ß receptors. In this study, we demonstrate that the clathrin- and caveolae-mediated endocytic pathways can converge during TGF-ß receptor endocytic trafficking. By tracking the intracellular dynamics of fluorescently-labeled TGF-ß type I receptor (TßRI), we found that after mediating TßRI internalization, certain clathrin-coated vesicles and caveolar vesicles are fused underneath the plasma membrane, forming a novel type of caveolin-1 and clathrin double-positive vesicles. Under the regulation of Rab5, the fused vesicles are targeted to early endosomes and thus deliver the internalized TßRI to the caveolin-1 and EEA1 double-positive early endosomes (caveolin-1-positive early endosomes). We further showed that the caveolin-1-positive early endosomes are positive for Smad3/SARA, Rab11 and Smad7/Smurf2, and may act as a multifunctional device for TGF-ß signaling and TGF-ß receptor recycling and degradation. Therefore, these findings uncover a novel scenario of endocytosis, the direct fusion of clathrin-coated and caveolae vesicles during TGF-ß receptor endocytic trafficking, which leads to the formation of the multifunctional sorting device, caveolin-1-positive early endosomes, for TGF-ß receptors.

20-Hydroxyeicosatetraenoic acid involved in endothelial activation and thrombosis.

Endothelial cells play an important role in the process of coagulation and the function of platelets. We have previously reported that 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite of arachidonic acid, increased platelet aggregation and induced hemostasis. The purpose of the present study is to investigate whether 20-HETE-mediated endothelial activation has effect on the coagulation and platelet aggregation. C57Bl/6 mice were treated with PBS or 20-HETE (20 µg/kg) for 2 h, and then we performed a carotid artery or femoral artery thrombosis model by FeCl3. Detection of blood flow indicated that 20-HETE pretreatment accelerated formation of thrombus in both common carotid artery and femoral artery. In vitro, the secretion and expression of von Willebrand factor (vWF) in cultured human umbilical vein endothelial cells (HUVECs) with 20-HETE stimulation were increased, subsequently. The protein level of vWF in HUVECs was decreased at 1 h but increased with prolonged treatment with 20-HETE (>4 h). In contrast, vWF in the culture medium was increased under administration of 20-HETE at 1 h. As a result, adhesion of platelets on HUVECs was significantly increased by 20-HETE. In HUVECs, the extracellular signal-regulated kinase (ERK) pathway was activated by 20-HETE in a dose-dependent manner, and the inhibitors of ERK and L-type Ca(2+) channel blocked the release of vWF mediated by 20-HETE. In conclusion, 20-HETE instigates endothelial activation and induces the expression and secretion of vWF via the activation of ERK and calcium channel and therefore triggers thrombosis.

Mammalian actin-binding protein 1/HIP-55 is essential for the scission of clathrin-coated pits by regulating dynamin-actin interaction.

Actin and dynamin work cooperatively to drive the invagination and scission of clathrin-coated pits (CCPs). However, little is known about the mechanism that orchestrates the spatiotemporal recruitment of dynamin and actin. Here, we have identified the mammalian actin-binding protein 1 (mAbp1; also called HIP-55 or SH3P7), which could bind to clathrin, actin, as well as dynamin, as an adaptor that links the dynamic recruitment of dynamin and actin for the scission of CCPs. Live-cell imaging reveals that mAbp1 is specifically recruited at a late stage of the long-lived CCPs. mAbp1 knockdown impaired CCP scission by reducing dynamin recruitment at the plasma membrane. However, actin disruption remarkably eliminates mAbp1 recruitment and thus dynamin recruitment. These data suggest that by binding to both clathrin and F-actin, mAbp1 is specifically recruited at a late stage of CCP formation, which subsequently recruits dynamin to CCPs.