CXCL5 activates CXCR2 in nociceptive sensory neurons to drive joint pain and inflammation in experimental gouty arthritis.

Gouty arthritis evokes joint pain and inflammation. Mechanisms driving gout pain and inflammation remain incompletely understood. Here we show that CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to drive gout pain and inflammation. CXCL5 expression was increased in ankle joints of gout arthritis model mice, whereas CXCR2 showed expression in joint-innervating sensory neurons. CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to trigger TRPA1 activation, resulting in hyperexcitability and pain. Neuronal CXCR2 coordinates with neutrophilic CXCR2 to contribute to CXCL5-induced neutrophil chemotaxis via triggering CGRP- and substance P-mediated vasodilation and plasma extravasation. Neuronal Cxcr2 deletion ameliorates joint pain, neutrophil infiltration and gait impairment in model mice. We confirmed CXCR2 expression in human dorsal root ganglion neurons and CXCL5 level upregulation in serum from male patients with gouty arthritis. Our study demonstrates CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and inflammation that expands our knowledge of immunomodulation capability of nociceptive sensory neurons.

Neutrophil-derived oxidative stress contributes to skin inflammation and scratching in a mouse model of allergic contact dermatitis via triggering pro-inflammatory cytokine and pruritogen production in skin.

Allergic contact dermatitis (ACD) is a common skin disease featured with skin inflammation and a mixed itch/pain sensation. The itch/pain causes the desire to scratch, affecting both physical and psychological aspects of patients. Nevertheless, the mechanisms underlying itch/pain sensation of ACD still remain elusive. Here, we found that oxidative stress and oxidation-related injury were remarkably increased in the inflamed skin of a mouse model of ACD. Reducing oxidative stress significantly attenuated itch/pain-related scratching, allokonesis and skin inflammation. RNA-Sequencing reveals oxidative stress contributes to a series of skin biological processes, including inflammation and immune response. Attenuating oxidative stress reduces overproduction of IL-1ß and IL-33, two critical cytokines involved in inflammation and pain/itch, in the inflamed skin of model mice. Exogenously injecting H2O2 into the neck skin of naïve mice triggered IL-33 overproduction in skin keratinocytes and induced scratching, which was reduced in mice deficient in IL-33 receptor ST2. ACD model mice showed remarkable neutrophil infiltration in the inflamed skin. Blocking neutrophil infiltration reduced oxidative stress and attenuated scratching and skin inflammation. Therefore, our study reveals a critical contribution of neutrophil-derived oxidative stress to skin inflammation and itch/pain-related scratching of ACD model mice via mechanisms involving the triggering of IL-33 overproduction in skin keratinocytes. Targeting skin oxidative stress may represent an effective therapy for ameliorating ACD.

Activation of Nrf2 antioxidant signaling alleviates gout arthritis pain and inflammation.

Excessive deposition of monosodium urate (MSU) crystal in the joint results in gout arthritis, which triggers severe pain and affects life quality. Oxidative stress is a pivotal mechanism that contributes to etiology of gout pain and inflammation. Here we investigated whether activating Nrf2, which plays important roles in regulating endogenous antioxidant response, would attenuate gout arthritis via promoting antioxidant signaling in joint tissues. Gout arthritis model was established by intra-articular injection of MSU (500 µg/ankle) into the right ankle joint of mouse. Pharmacologically activating Nrf2 by activator oltipraz (50, 100 or 150 mg/kg, intraperitoneal) at 1 h before and 5, 23, 47 h after model establishment dose-dependently inhibited joint inflammation, mechanical and heat hypersensitivities in model mice. Oltipraz (100 mg/kg) reversed gait impairments without altering locomotor activity and reduced neutrophil infiltrations in ankle joints. In vitro studies revealed oltipraz (25 µM) inhibited MSU-induced ROS production in mouse macrophages and improved mitochondrial bioenergetics impairments caused by MSU. In vivo ROS imaging combined with biochemical assays confirmed the antioxidant effects of oltipraz on model mice. Nrf2 activation inhibited pro-inflammatory cytokine overproduction in ankle joint and attenuated the overexpression and enhancement in TRPV1 channel in DRG neurons innervating hind limb. Therapeutic effects of oltipraz were abolished by inhibiting Nrf2 or in Nrf2 knockout mice. These results suggest pharmacologically activating Nrf2 alleviates gout pain, gait impairments, inflammation and peripheral sensitization via Nrf2-dependent antioxidant mechanism. Targeting Nrf2 may represent a novel treatment option for gout arthritis.

Electroacupuncture improves gout arthritis pain via attenuating ROS-mediated NLRP3 inflammasome overactivation.

BACKGROUND: Gout results from disturbed uric acid metabolism, which causes urate crystal deposition in joints and surrounding tissues. Gout pain management is largely limited to colchicine and nonsteroidal anti-inflammatory drugs. Constant usage of these medications leads to severe side effects. We previously showed electroacupuncture (EA) is effective for relieving pain in animal model of gout arthritis. Here we continued to study the mechanisms underlying how EA alleviates gout pain. METHODS: Monosodium urate was injected into ankle joint to establish gout arthritis model in mice. EA or sham EA was applied at ST36 and BL60 acupoints of model animals. Biochemical assays, immunostaining, live cell Ca2+ imaging and behavioral assays were applied. RESULTS: Model mice displayed obvious mechanical allodynia, accompanied with gait impairments. EA attenuated mechanical hypersensitivities and improved gait impairments. EA reduced the overexpression of NLRP3 inflammasome signaling molecules in ankle joints of model animals. EA-induced anti-allodynia, as well as inhibition on NLRP3 inflammasome, were mimicked by antagonizing but abolished by activating NLRP3 inflammasome via pharmacological methods. EA attenuated oxidative stress, an upstream signaling of NLRP3 inflammasome in ankle joints of model mice. Exogenously increasing oxidative stress abolished EA's inhibitory effect on NLRP3 inflammasome and further reversed EA's anti-allodynic effect. EA reduced neutrophil infiltrations in ankle joint synovium, a major mechanism contributing to oxidative stress in gout. Pharmacological blocking NLRP3 inflammasome or EA reduced TRPV1 channel overexpression in dorsal root ganglion (DRG) neurons. Ca2+ imaging confirmed that EA could reduce functional enhancement in TRPV1 channel in DRG neurons during gout. CONCLUSIONS: Our results demonstrate that EA reduces gout pain possibly through suppressing ROS-mediated NLRP3 inflammasome activation in inflamed ankle joints and TRPV1 upregulation in sensory neurons, supporting EA as a treatment option for gout pain.

IL-33/ST2 signaling in pain and itch: Cellular and molecular mechanisms and therapeutic potentials.

Pain is a cardinal feature of many diseases. Chronic pain poses heavy burdens to the suffering patients, both physically and mentally. However, current mainstream medications for chronic pain, including opioids, antidepressants and non-steroid anti-inflammatory drugs are sometimes inefficient for chronic pain management and may cause side effects that limit long term usage. IL-33 belongs to IL-1 cytokine family and it exerts biological activities through binding to its specific receptor ST2. IL-33/ST2 signaling is very important in both innate and adaptive immunity. Emerging evidence indicates IL-33/ST2 signaling regulates pain in both immune and somatosensory systems through promoting neuro-immune or neuron-glia crosstalk, neuroinflammation and neuronal hyperexcitability. Some very latest studies indicate a vital part of IL-33/ST2 in mediating chronic itch. This work aims to overview the existing knowledge regarding the mechanisms of IL-33/ST2 involvement in pain and itch conditions, considering their potential similarities. We also summarized some key findings obtained from clinical studies. The targeting of IL-33/ST2 signaling holds promise for the development of novel therapeutic modalities in the management of pain and itch.

Characterization of pain-related behaviors and gene expression profiling of peripheral sensory ganglia in a mouse model of acute ankle sprain.

Introduction: Lateral ankle sprain (LAS) is a very common type of joint injury. It occurred with high incidence among general population and especially among individuals participating sports and outdoor activities. A certain proportion of individuals who once developed LAS may suffer persistent ankle pain that affects daily activities. However, the mechanisms underlying LAS-induced pain still remained largely unknown. Methods: We established a LAS mouse model and systematically evaluated the pain-related behaviors in this mouse model. RNA sequencing (RNA-Seq), combined with bioinformatics analysis, was undertaken to explore gene expression profiles. Immunostaining was used to study glial cell and neuron activation in ipsilateral spinal cord dorsal horn (SCDH) of LAS model mice. Ibuprofen was used to treat LAS model mice. Results: The LAS model mice developed obvious signs of mechanical and heat hypersensitivities as well as gait impairments in ipsilateral hind paws. Besides, LAS model mice developed signs of pain-related emotional disorder, including pain-induced aversion. By RNA-Seq, we were able to identify certain differentially expressed genes and signaling pathways that might contribute to pain mechanisms of LAS mouse model. In addition, LAS model mice showed increased c-Fos and p-ERK immunoreactivity as well as astrocyte and microglia overactivation in ipsilateral spinal cord dorsal horn, indicating central sensitization might occur. Finally, LAS model mice respond to ibuprofen, a drug clinically used to treat ankle sprain pain. Conclusion: Our study found LAS model mice may be used as a preclinical animal model for screening novel targets or therapies for ankle sprain. Thus, the study may further help to understand molecular mechanisms contributing to ankle sprain-induced pain.

Influence of a new abutment design concept on the biomechanics of peri-implant bone, implant components, and microgap formation: a finite element analysis.

BACKGROUND: A new two-piece abutment design consisting of an upper prosthetic component and tissue-level base has been introduced; however, the biomechanical behavior of such a design has not been documented. This study aimed to investigate the effect of a two-piece abutment design on the stress in the implant components and surrounding bone, as well as its influence on microgap formation. METHODS: To simulate the implant models in the mandibular left first molar area, we established nine experimental groups that included three bone qualities (type II, III, and IV) and three implant-abutment designs (internal bone level, tissue level, and a two-piece design). After the screw was preloaded, the maximum occlusal (600 N) and masticatory (225 N) forces were established. Finite element analysis was performed to analyze the maximum and minimum principal stresses on the peri-implant bone; the von Mises stresses in the implants, abutments, bases, and screws, and the microgaps at the implant-abutment, implant-base, and base-abutment interfaces. RESULTS: For all three loading methods, the two-piece abutment design and bone-level connection exhibited similarities in the maximum and minimum principal stresses in the peri-implant bone. The von Mises stresses in both screws and bases were greater for the two-piece design than for the other connection types. The smallest microgap was detected in the tissue-level connection; the largest was observed at the implant-base interface in the two-piece design. CONCLUSIONS: The present study found no evidence that the abutment design exerts a significant effect on peri-implant bone stress. However, the mechanical effects associated with the base and screws should be noted when using a two-piece abutment design. The two-piece abutment design also had no advantage in eliminating the microgap.

CXCL13 contributes to chronic pain of a mouse model of CRPS-I via CXCR5-mediated NF-κB activation and pro-inflammatory cytokine production in spinal cord dorsal horn.

BACKGROUND: Complex regional pain syndrome type-I (CRPS-I) causes excruciating pain that affect patients' life quality. However, the mechanisms underlying CRPS-I are incompletely understood, which hampers the development of target specific therapeutics. METHODS: The mouse chronic post-ischemic pain (CPIP) model was established to mimic CRPS-I. qPCR, Western blot, immunostaining, behavioral assay and pharmacological methods were used to study mechanisms underlying neuroinflammation and chronic pain in spinal cord dorsal horn (SCDH) of CPIP mice. RESULTS: CPIP mice developed robust and long-lasting mechanical allodynia in bilateral hindpaws. The expression of inflammatory chemokine CXCL13 and its receptor CXCR5 was significantly upregulated in ipsilateral SCDH of CPIP mice. Immunostaining revealed CXCL13 and CXCR5 was predominantly expressed in spinal neurons. Neutralization of spinal CXCL13 or genetic deletion of Cxcr5 (Cxcr5-/-) significantly reduced mechanical allodynia, as well as spinal glial cell overactivation and c-Fos activation in SCDH of CPIP mice. Mechanical pain causes affective disorder in CPIP mice, which was attenuated in Cxcr5-/- mice. Phosphorylated STAT3 co-expressed with CXCL13 in SCDH neurons and contributed to CXCL13 upregulation and mechanical allodynia in CPIP mice. CXCR5 coupled with NF-κB signaling in SCDH neurons to trigger pro-inflammatory cytokine gene Il6 upregulation, contributing to mechanical allodynia. Intrathecal CXCL13 injection produced mechanical allodynia via CXCR5-dependent NF-κB activation. Specific overexpression of CXCL13 in SCDH neurons is sufficient to induce persistent mechanical allodynia in naïve mice. CONCLUSIONS: These results demonstrated a previously unidentified role of CXCL13/CXCR5 signaling in mediating spinal neuroinflammation and mechanical pain in an animal model of CRPS-I. Our work suggests that targeting CXCL13/CXCR5 pathway may lead to novel therapeutic approaches for CRPS-I.

Electroacupuncture Ameliorates Mechanical Allodynia of a Rat Model of CRPS-I via Suppressing NLRP3 Inflammasome Activation in Spinal Cord Dorsal Horn Neurons.

Complex regional pain syndrome type-I (CRPS-I) is a chronic neurological disorder that results in severe pain and affects patients' life quality. Conventional therapies usually lack effectiveness. Electroacupuncture (EA) is an effective physical therapy for relieving CRPS-I pain. However, the mechanism underlying EA-induced analgesia on CRPS-I still remain unknown. Spinal NLRP3 inflammasome was recently identified to contribute to pain and neuroinflammation in a rat model of CRPS-I by our group. Here, we aimed to study whether EA could inhibit spinal NLRP3 inflammasome activation, thus resulting in pain relief and attenuation of spinal neuroinflammation in the rat model of CRPS-I. We established the rat chronic post-ischemic pain (CPIP) model to mimic CRPS-I. CPIP rats developed remarkable mechanical allodynia that could be relieved by daily EA intervention. NLRP3 inflammasome was activated in spinal cord dorsal horn (SCDH) of CPIP rats, accompanied with over-production of pro-inflammatory cytokine IL-1ß. Immunostaining revealed that the cellular distribution of NLRP3 was predominantly located in SCDH neurons. Pharmacological activation of NLRP3 inflammasome per se is sufficient to produce persistent mechanical allodynia in naïve animals, whereas blocking NLRP3 inflammasome attenuates mechanical allodynia of CPIP rats. EA exclusively reduced NLRP3 overexpression in SCDH neurons and attenuated spinal glial cell over-activation in CPIP rats. EA-induced anti-allodynia with attenuation of spinal glial cell over-activation were all mimicked by intrathecal blocking NLRP3 inflammasome and reversed by activating NLRP3 inflammasome, respectively, through pharmacological methods. Finally, spinal blocking IL-1ß attenuated mechanical allodynia and spinal glial cell over-activation in CPIP rats, resembling the effects of EA. In all, these results demonstrate that spinal NLRP3 inflammasome activation contributes to mechanical allodynia of the rat model of CRPS-I and EA ameliorates mechanical allodynia through inhibiting NLRP3 inflammasome activation in SCDH neurons. Our study further supports EA can be used as an effective treatment for CRPS-I.

Nrf2 Activation Mediates Antiallodynic Effect of Electroacupuncture on a Rat Model of Complex Regional Pain Syndrome Type-I through Reducing Local Oxidative Stress and Inflammation.

Complex regional pain syndrome type-I (CRPS-I) represents a type of neurovascular condition featured by severe pain in affected extremities. Few treatments have proven effective for CRPS-I. Electroacupuncture (EA) is an effective therapy for pain relief. We explored the mechanism through which EA ameliorates pain in a rat CRPS-I model. The chronic postischemic pain (CPIP) model was established using Sprague-Dawley rats to mimic CRPS-I. We found that oxidative stress-related biological process was among the predominant biological processes in affected hindpaw of CPIP rats. Oxidative stress occurred primarily in local hindpaw but not in the spinal cord or serum of model rats. Antioxidant N-acetyl cysteine (NAC) attenuated mechanical allodynia and spinal glia overactivation in CPIP model rats, whereas locally increasing oxidative stress is sufficient to induce chronic pain and spinal glia overactivation in naive rats. EA exerted remarkable antiallodynia on CPIP rats by reducing local oxidative stress via enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Pharmacological blocking Nrf2 abolished antioxidative and antiallodynic effects of EA. EA reduced spinal glia overactivation, attenuated the upregulation of inflammatory cytokines, reduced the enhanced TRPA1 channel activity in dorsal root ganglion neurons innervating the hindpaws, and improved blood flow dysfunction in hindpaws of CPIP rats, all of which were mimicked by NAC treatment. Thus, we identified local oxidative injury as an important contributor to pathogenesis of animal CRPS-I model. EA targets local oxidative injury by enhancing endogenous Nrf2-mediated antioxidative mechanism to relieve pain and inflammation. Our study indicates EA can be an alternative option for CRPS-I management.

Genome-Wide Expression Profiling by RNA-Sequencing in Spinal Cord Dorsal Horn of a Rat Chronic Postsurgical Pain Model to Explore Potential Mechanisms Involved in Chronic Pain.

Background: Chronic postsurgical pain (CPSP) is common among patients receiving major surgeries. CPSP produces suffering in patients, both physically and mentally. However, the mechanisms underlying CPSP remain elusive. Here, a genome-wide expression profiling of ipsilateral spinal cord dorsal horn (SCDH) was performed to identify potential genes related with CPSP. Methods: A rat skin/muscle incision and retraction (SMIR) model was established to induce CPSP. Immunostaining was used to study glial cell and neuron activation in ipsilateral SCDH of SMIR model rats. RNA sequencing (RNA-Seq), combined with bioinformatics analysis, was undertaken to explore gene expression profiles. qPCR was applied to validate the expression of some representative genes. Results: The SMIR model rats developed persistent mechanical allodynia in ipsilateral hindpaw for up to 14 days. Ipsilateral SCDH of SMIR rats showed remarkable glial cell and neuron activation. A number of differentially expressed genes (DEGs) were identified in ipsilateral SCDH of SMIR rats by RNA-Seq. qPCR confirmed expression of some representative DEGs. Bioinformatics indicated that chemical synaptic transmission, sensory perception of pain and neuroactive ligand-receptor interaction were predominant functions. We compared our dataset with human pain-related genes and found that several genes exclusively participate in pain modulation and mechanisms. Conclusion: Our study provided novel understandings of the molecular mechanisms possibly contributing to CPSP. These findings may offer new targets for future treatment of CPSP.

Exploring neuronal mechanisms involved in the scratching behavior of a mouse model of allergic contact dermatitis by transcriptomics.

BACKGROUND: Allergic contact dermatitis (ACD) is a common skin condition characterized by contact hypersensitivity to allergens, accompanied with skin inflammation and a mixed itch and pain sensation. The itch and pain dramatically affects patients' quality of life. However, still little is known about the mechanisms triggering pain and itch sensations in ACD. METHODS: We established a mouse model of ACD by sensitization and repetitive challenge with the hapten oxazolone. Skin pathological analysis, transcriptome RNA sequencing (RNA-seq), qPCR, Ca2+ imaging, immunostaining, and behavioral assay were used for identifying gene expression changes in dorsal root ganglion innervating the inflamed skin of ACD model mice and for further functional validations. RESULTS: The model mice developed typical ACD symptoms, including skin dryness, erythema, excoriation, edema, epidermal hyperplasia, inflammatory cell infiltration, and scratching behavior, accompanied with development of eczematous lesions. Transcriptome RNA-seq revealed a number of differentially expressed genes (DEGs), including 1436-DEG mRNAs and 374-DEG-long noncoding RNAs (lncRNAs). We identified a number of DEGs specifically related to sensory neuron signal transduction, pain, itch, and neuroinflammation. Comparison of our dataset with another published dataset of atopic dermatitis mouse model identified a core set of genes in peripheral sensory neurons that are exclusively affected by local skin inflammation. We further found that the expression of the pain and itch receptor MrgprD was functionally upregulated in dorsal root ganglia (DRG) neurons innervating the inflamed skin of ACD model mice. MrgprD activation induced by its agonist ß-alanine resulted in exaggerated scratching responses in ACD model mice compared with naïve mice. CONCLUSIONS: We identified the molecular changes and cellular pathways in peripheral sensory ganglia during ACD that might participate in neurogenic inflammation, pain, and itch. We further revealed that the pain and itch receptor MrgprD is functionally upregulated in DRG neurons, which might contribute to peripheral pain and itch sensitization during ACD. Thus, targeting MrgprD may be an effective method for alleviating itch and pain in ACD.

Gene Expression Profiling of Contralateral Dorsal Root Ganglia Associated with Mirror-Image Pain in a Rat Model of Complex Regional Pain Syndrome Type-I.

BACKGROUND: Mirror-image pain (MIP), which develops from the healthy body region contralateral to the actual injured site, is a mysterious pain phenomenon accompanying many chronic pain conditions, such as complex regional pain syndrome (CRPS). However, the pathogenesis of MIP still remains largely unknown. The purpose of this study is to perform an expression profiling to identify genes related to MIP in an animal model of CRPS-I. METHODS: We established a rat chronic post-ischemic pain (CPIP) model to mimic human CRPS-I. RNA-sequencing (RNA-Seq), bioinformatics, qPCR, immunostaining, and animal behavioral assays were used to screen potential genes in the contralateral dorsal root ganglia (DRG) that may be involved in MIP. RESULTS: The CPIP model rats developed robust and persistent MIP in contralateral hind paws. Bilateral DRG neurons did not exhibit obvious neuronal damage. RNA-Seq of contralateral DRG from CPIP model rats identified a total 527 differentially expressed genes (DEGs) vs sham rats. The expression changes of several representative DEGs were further verified by qPCR. Bioinformatics analysis indicated that the immune system process, innate immune response, and cell adhesion were among the mostly enriched biological processes, which are important processes involved in pain sensitization, neuroinflammation, and chronic pain. We further identified DEGs potentially involved in pain mechanisms or enriched in small- to medium-sized sensory neurons or TRPV1-lineage nociceptors. By comparing with published datasets summarizing genes enriched in pain mechanisms, we sorted out a core set of genes which might contribute to nociception and the pain mechanism in MIP. CONCLUSION: We provided by far the first study to profile gene expression changes and pathway analysis of contralateral DRG for the studying of MIP mechanisms. This work may provide novel insights into understanding the mysterious mechanisms underlying MIP.

Transcriptome profiling of long noncoding RNAs and mRNAs in spinal cord of a rat model of paclitaxel-induced peripheral neuropathy identifies potential mechanisms mediating neuroinflammation and pain.

BACKGROUND: Paclitaxel is a widely prescribed chemotherapy drug for treating solid tumors. However, paclitaxel-induced peripheral neuropathy (PIPN) is a common adverse effect during paclitaxel treatment, which results in sensory abnormalities and neuropathic pain among patients. Unfortunately, the mechanisms underlying PIPN still remain poorly understood. Long noncoding RNAs (lncRNAs) are novel and promising targets for chronic pain treatment, but their involvement in PIPN still remains unexplored. METHODS: We established a rat PIPN model by repetitive paclitaxel application. Immunostaining, RNA sequencing (RNA-Seq) and bioinformatics analysis were performed to study glia cell activation and explore lncRNA/mRNA expression profiles in spinal cord dorsal horn (SCDH) of PIPN model rats. qPCR and protein assay were used for further validation. RESULTS: PIPN model rats developed long-lasting mechanical and thermal pain hypersensitivities in hind paws, accompanied with astrocyte and microglia activation in SCDH. RNA-Seq identified a total of 814 differentially expressed mRNAs (DEmRNA) (including 467 upregulated and 347 downregulated) and 412 DElncRNAs (including 145 upregulated and 267 downregulated) in SCDH of PIPN model rats vs. control rats. Functional analysis of DEmRNAs and DElncRNAs identified that the most significantly enriched pathways include immune/inflammatory responses and neurotrophin signaling pathways, which are all important mechanisms mediating neuroinflammation, central sensitization, and chronic pain. We further compared our dataset with other published datasets of neuropathic pain and identified a core set of immune response-related genes extensively involved in PIPN and other neuropathic pain conditions. Lastly, a competing RNA network analysis of DElncRNAs and DEmRNAs was performed to identify potential regulatory networks of lncRNAs on mRNA through miRNA sponging. CONCLUSIONS: Our study provided the transcriptome profiling of DElncRNAs and DEmRNAs and uncovered immune and inflammatory responses were predominant biological events in SCDH of the rat PIPN model. Thus, our study may help to identify promising genes or signaling pathways for PIPN therapeutics.

Electroacupuncture Alleviates Mechanical Allodynia of a Rat Model of CRPS-I and Modulates Gene Expression Profiles in Dorsal Root Ganglia.

Complex regional pain syndrome type-I (CRPS-I) is chronic neurological disorder accompanied with devastating pain. Most conventional medical treatments lack effectiveness, making CRPS-I a challenging clinical condition. Electroacupuncture (EA) showed effectiveness in alleviating the pain symptoms of CRPS-I patients. However, the molecular mechanisms underlying EA's therapeutic effect are still not well-understood. Here, we established the rat chronic post-ischemic pain (CPIP) model to mimic CRPS-I and performed repetitive EA on bilateral hind limbs of the CPIP model rats. We then performed RNA-sequencing (RNA-Seq) to study the differences in gene expression, gene networks, and molecular pathways in ipsilateral DRGs innervating the hind limb of the CPIP model rats with and without repetitive EA treatment. Our results found that repetitive EA treatment significantly alleviated mechanical allodynia in bilateral hind limbs of CPIP model rats. RNA-Seq analysis indicated that EA modulated the expression of multiple genes and gene networks in the DRGs of CPIP model rats. Further bioinformatics analysis identified the up-regulation of an array of genes involved in biological process such as neutrophil chemotaxis and immune response in the DRGs of CPIP model rats after EA treatment. Thus, these results suggest that EA may alleviate pain response in CPIP model rats via regulating multiple genes. Our work may help to further advance the understandings of the molecular mechanisms underlying EA's therapeutic effects on CRPS-I and help to identify novel targets for CRPS-I treatment.

The impact of the coronavirus (COVID-19) pandemic on elective paediatric otolaryngology outpatient services - An analysis of virtual outpatient clinics in a tertiary referral centre using the modified paediatric otolaryngology telemedicine satisfaction survey (POTSS).

INTRODUCTION: Virtual outpatient clinics (VOPC) have been integrated into both paediatric and based adult outpatient services due to a multitude of factors, including increased demand for services, technological advances and rising morbidity secondary to ageing populations. The novel coronavirus disease (COVID-19) has accentuated pressures on the National Health Service (NHS) infrastructure, particularly elective services, whilst radically altering patterns of practice. AIM: To evaluate the impact of the COVID-19 pandemic on paediatric otolaryngology outpatient services whilst collating patient feedback to elicit long-term sustainability post COVID-19. METHOD: A retrospective analysis of VOPCs was undertaken at a tertiary paediatric referral centre over a 3-month capture period during the COVID-19 pandemic. Demographic, generic clinic (presenting complaint, new vs. follow-up, consultation type), as well as outcome data (medical or surgical intervention, discharge vs. ongoing review, onward referral, investigations, and conversion to face-to-face) was collated. Additionally a modified 15-point patient satisfaction survey was created. The Paediatric Otolaryngology Telemedicine Satisfaction survey (POTSS), was an adaptation of 4 validated patient satisfaction tools including the General Medical Council (GMC) patient questionnaire, the telehealth satisfaction scale (TESS), the telehealth usability questionnaire (TUQ), and the telemedicine satisfaction and usefulness questionnaire (TSUQ). RESULTS: Of 514 patients reviewed virtually over a 3-month period, 225 (45%) were randomly selected to participate, of which 200 met our inclusion criteria. The most common mode of consultation was telephony (92.5%, n = 185). Non-attendance rates were reduced when compared to face-to-face clinics during an equivalent period prior to the COVID-19 pandemic. A significant proportion of patients (29% compared to 26% pre-VOPC) were discharged to primary care. Nine percent were listed for surgery compared to 19% pre-VOPC. A subsequent face-to-face appointment was required in 10% of participants. Overall, the satisfaction when assessing the doctor-patient relationship, privacy & trust, as well as consultation domains was high, with the overwhelming majority of parents' content with the future integration and participation in VOPCs. CONCLUSION: An evolving worldwide pandemic has accelerated the need for healthcare services to reform in order to maintain a steady flow of patients within an elective outpatient setting without compromising patient care. Solutions must be sustainable long-term to account for future disruptions, whilst accounting for evolving patient demographics. Our novel survey has demonstrated the vast potential that the integration of VOPCs can offer paediatric otolaryngology services within a carefully selected cohort of patients.

Sexual knowledge, attitude and associated factors among primary and middle school students / 中国学校卫生

Objective@#To understand the awareness of sexual knowledge among primary and secondary school students, as well as their attitudes towards school sex education and to provide a reference for school-based sex education.@*Methods@#A total of 5 531 primary and secondary school students were selected from Beijing, Chongqing, Heilongjiang (Harbin and Jiamusi) and Hubei (Wuhan and Xiaogan) by stratified cluster sampling and were investigated with self-reported questionnaire.@*Results@#Sex-related knowledge scored 62.33±19.35, with a pass rate of 61.9%, and the excellent rate 17.5%. Sexual knowledge of junior high school students scored 64.30±19.07, with the pass rate of 64.7%, and the excellent rate 22.0%. A large proportion of primary students reported unaware of pubertal growth and HIV/AIDS-related knowledge, and a large proportion of junior high students unaware of reproductive physiology. Multivariate Logistic regression analysis showed region, grade, gender, and suburban areas were related to the level of sexual knowledge(P<0.05). More than 76.0% primary students and 85.9% middle school students agreed on the importance of school sexuality education. 59.7% of primary school students and 73.3% of junior high school students hoped to include school sexuality education in compulsory education courses; 59.8% of primary school students and 68.3% of junior high school students felt that school sexuality education should be equipped with specialized teachers.@*Conclusion@#Chinese primary and secondary school students are lack of sexual knowledge. As students have strong wills to get more information on sexual knowledge, schools should provide them with more comprehensive and effective sex education through appropriate courses and activities.

A social ecological approach to understanding of youth injury associated factors and health implications / 中国学校卫生

Objective@#To explore the related factors and working way of adolescent injury,and to provide a basis for the effective prevention and intervention of adolescent injury.@*Methods@#The framework of the questionnaire in this study was developed based on the Social Ecology Model. A cross-sectional survey was conducted on a valid sample of 4 309 students from 8 junior high schools and 8 senior high schools in Beijing and Zhongshan city respectively, using stratified random cluster sampling method. Students from grade 7 to grade 12 were invited to participate and investigated with injury prevalence.@*Results@#The incidence of adolescent injury by person and by person-time was 15.53% and 22.49% respectively, and there were differences by sex, age and regions(χ2=15.92，11.45，20.33，P<0.05). The occurrence of adolescent injury was affected by adolescent psychological behavior and social environment through different underlying pathways. The intrapersonal factors and perception of environmental safety showed direct effects on the adolescents’ injuries (effect size was 0.29 and 0.05 respectively, P<0.05).@*Conclusion@#Adolescent injury is associated with diverse factors and pathways in a synergistic and complex manner, suggesting that a three-dimensional and diverse strategy should be taken to intervene the injures.

Comparative analysis of international and chinese policy on sexuality education / 中国学校卫生

Abstract@#Sexuality education policy is an important part of guiding and guaranteeing the implementation of sexuality education. At present, China has not formulated an independent sexuality education policy, but stipulates the content of sexuality education into the health education standard, namely the guidelines for health education in primary and secondary schools. globally, International Technical Guidance on Sexuality Education (revised edition) formulated by UNESCO provides a reference for countries around the world to carry out sexuality education. This research adopts the basic method of comparative pedagogy to make an in-depth comparative analysis of the above two programs, in order to understand their similarities and differences in the goals, contents, implementation and evaluation of sexuality education, and to provide reference for further improving the content of sexuality education in China and promoting the implementation of sexuality education in schools.

Analysis of the needs of students, parents and teachers for comprehensive sexuality education content / 中国学校卫生

Objective@#To understand the needs of primary and secondary school students, parents and teachers for comprehensive sexuality education content, and to explore the applicability of comprehensive sexuality education content in China.@*Methods@#By using the method of stratified cluster sampling, 5 571 primary and middle school students and 4 835 parents from Beijing, Chongqing, Heilongjiang (Harbin and Jiamusi) and Hubei (Wuhan and Xiaogan) were selected for questionnaire survey. Depending on the physical health monitoring points of various provinces and cities, 176 sexuality education related teachers in nine regions were surveyed. The development of the questionnaire was based on the content framework of comprehensive sexuality education proposed in the International Technical Guidelines for Sexuality Education.@*Results@#Students had a higher demand for knowledge on the concepts of "relationship" (53.4% for primary school students, 57.6% for junior high school students) and "health and well-being skills" (71.1% for primary school students, 55.9% for junior high school students). Parents had higher demand for most comprehensive sexuality education content with the exception of lower need for "sex and sexual behavior (74.7% of primary school parents, 80.8% of junior high school parents)" and "sexual and reproductive health (primary parents 74.3%, junior high school parents 75.8%)". Teachers had a high demand for most comprehensive sexuality education content, but primary school teachers had a lower need for "values, rights, culture and sex(65.9%)", "sex and sexuality(60.1%)" and "sexual and reproductive health(66.8%)". The results of correspondence analysis showed that junior middle school teachers had the highest demand for comprehensive education content, followed by primary school parents, junior middle school parents, primary school teachers, junior middle school students and primary school students.@*Conclusion@#Teachers and parents have a higher demand for most comprehensive sexuality education content, while lower demand for some relatively sensitive content. Students have a relatively low demand for comprehensive sexuality education content. It is recommended to further improve the content of school sexuality education based on the actual needs of China.