Contribution of inwardly rectifying potassium channel 4.1 in orofacial neuropathic pain: Regulation of pannexin 3 via the reactive oxygen species-activated P38 MAPK signal pathway.

The involvement of inwardly rectifying potassium channel 4.1 (Kir4.1) in neuropathic pain has been established. However, there is limited understanding of the downstream mechanism through which Kir4.1 contributes to orofacial neuropathic pain. The objective of this study was to examine the regulation of Kir4.1 on the expression of pannexin 3 (Panx3) in the trigeminal ganglion (TG) and the underlying mechanism in the context of orofacial neuropathic pain caused by chronic constriction injury of the infraorbital nerve (CCI-ION). The study observed a significant increase in Panx3 expression in the TG of mice with CCI-ION. Inhibition of Panx3 in the TG of CCI-ION mice resulted in alleviation of orofacial mechanical allodynia. Furthermore, conditional knockdown (CKD) of Kir4.1 in the TG of both male and female mice led to mechanical allodynia and upregulation of Panx3 expression. Conversely, overexpression of Kir4.1 decreased Panx3 levels in the TG and relieved mechanical allodynia in CCI-ION mice. In addition, silencing Kir4.1 in satellite glial cells (SGCs) decreased Panx3 expression and increased the phosphorylation of P38 MAPK. Moreover, silencing Kir4.1 in SGCs increased the levels of reactive oxygen species (ROS). The elevated phosphorylation of P38 MAPK resulting from Kir4.1 silencing was inhibited by using a superoxide scavenger known as the tempol. Silencing Panx3 in the TG in vivo attenuated the mechanical allodynia caused by Kir4.1 CKD. In conclusion, these findings suggest that the reduction of Kir4.1 promotes the expression of Panx3 by activating the ROS-P38 MAPK signalling pathway, thus contributing to the development of orofacial neuropathic pain.

Development of an online calculator for the prediction of seizure freedom following pediatric hemispherectomy using the Hemispherectomy Outcome Prediction Scale (HOPS).

OBJECTIVES: Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy. METHODS: Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom at three time points (1-, 2- and 5- years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops-calculator.com/). RESULTS: The selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral fluorodeoxyglucose-positron emission tomography [FDG-PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non-lesional MRI, non-stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE: Online calculators are useful, cost-free tools that can assist physicians in risk estimation and inform joint decision-making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.

Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

Neuromuscular electrical stimulation of humeral adductors in subjects with rotator cuff tear.

INTRODUCTION: In symptomatic patients with rotator cuff tear, MRI and radiographic studies have ascribed the pain symptom to insufficient humeral head depression during arm elevations. The arm adductors such as the teres major and pectoralis major may contribute to depression of the humerus head during arm elevations. Researchers have demonstrated that neuromuscular electrical stimulation (NMES) of the serratus anterior and lower trapezius can control scapular motions and improve acromiohumeral distance. It is unknown, however, if adductor neuromuscular training could help patients with rotator cuff tear. MATERIALS AND METHODS: A cross-sectional study of NMES of the teres major and pectoralis major was conducted on 30 symptomatic subjects with rotator cuff tear. We measured the acromiohumeral distance by ultrasonography and scapular kinematics during arm elevation with a three-dimensional motion tracking system. RESULTS: The acromiohumeral distance significantly increased during NMES of the teres major (0.73 mm, p < 0.001). However, the distance significantly decreased with NMES of the pectoralis major (0.78 mm, p < 0.001). Additionally, scapular upward rotation was greater during NMES of the teres major than during NMES of the pectoralis major (3.4°, p < 0.001). Scapular external rotation decreased significantly more during NMES of the pectoralis major than during NMES of the teres major (1.6°, p = 0.003). CONCLUSIONS: NMES of the teres major can increase acromiohumeral distance and scapular upward rotation during arm elevation. However, the decreased upward and external rotation of the scapula during arm elevation with NMES of the pectoralis major may be associated with subacromial impingement.

Metabotropic glutamate receptor 5-mediated inhibition of inward-rectifying K+ channel 4.1 contributes to orofacial ectopic mechanical allodynia following inferior alveolar nerve transection in male mice.

Inward-rectifying K+ channel 4.1 (Kir4.1), which regulates the electrophysiological properties of neurons and glia by affecting K+ homeostasis, plays a critical role in neuropathic pain. Metabotropic glutamate receptor 5 (mGluR5) regulates the expression of Kir4.1 in retinal Müller cells. However, the role of Kir4.1 and its expressional regulatory mechanisms underlying orofacial ectopic allodynia remain unclear. This study aimed to investigate the biological roles of Kir4.1 and mGluR5 in the trigeminal ganglion (TG) in orofacial ectopic mechanical allodynia and the role of mGluR5 in Kir4.1 regulation. An animal model of nerve injury was established via inferior alveolar nerve transection (IANX) in male C57BL/6J mice. Behavioral tests indicated that mechanical allodynia in the ipsilateral whisker pad lasted at least 14 days after IANX surgery and was alleviated by the overexpression of Kir4.1 in the TG, as well as intraganglionic injection of an mGluR5 antagonist (MPEP hydrochloride) or a protein kinase C (PKC) inhibitor (chelerythrine chloride); Conditional knockdown of the Kir4.1 gene downregulated mechanical thresholds in the whisker pad. Double immunostaining revealed that Kir4.1 and mGluR5 were co-expressed in satellite glial cells in the TG. IANX downregulated Kir4.1 and upregulated mGluR5 and phosphorylated PKC (p-PKC) in the TG; Inhibition of mGluR5 reversed the changes in Kir4.1 and p-PKC that were induced by IANX; Inhibition of PKC activation reversed the downregulation of Kir4.1 expression caused by IANX (p < .05). In conclusion, activation of mGluR5 in the TG after IANX contributed to orofacial ectopic mechanical allodynia by suppressing Kir4.1 via the PKC signaling pathway.

Alteration in coracohumeral ligament and distance in people with symptoms of subcoracoid impingement.

BACKGROUND: Differentiation between subacromial impingement versus subcoracoid impingement are important for the treatment target. We evaluated the correlations between coracohumeral ligament (CHL) thickness and distance (CHD) and characterized the CHL and subscapularis (SSC) in subcoracoid impingement subjects. METHODS: An observational, cross-sectional study was carried out. Twenty subcoracoid impingement subjects and age/gender matched controls were assessed in 4 different shoulder positions by ultrasonography. RESULTS: Moderate correlations between CHL thickness with CHD (r = 0.455 in neutral rotation, p = 0.044; r = 0.483 in interior rotation, p = 0.031) were found in subacromial subjects. Subcoracoid impingement subjects had greater CHL thickness (difference = 0.3 mm, effect size = 0.85, p = 0.006), SSC tendon thickness (difference = 0.7 mm, effect size = 0.92, p = 0.01) and SSC/CHD occupation ratio (difference = 8%, effect size = 0.95, p = 0.005) compared with the control. CONCLUSIONS: Coracohumeral distance is related to ligament thickness, especially in subacromial impingement subjects. Increased coracohumeral ligament and subscapularis thickness as well as decreased subscapularis/coracohumeral distance occupation ratio are characterized in subcoracoid impingement subjects. These quantitative measurements can be useful in identifying patients at risk of subcoracoid impingement from subacromial impingement.

Pitching Biomechanics and Shoulder Function in Baseball Pitchers with Scapular Dyskinesis.

The primary purpose was to investigate the influence of scapular dyskinesis (SD) on pitching biomechanics and shoulder function in high school baseball pitchers. The secondary purpose was to identify possible factors associated with shoulder function in pitchers with SD. Thirty-eight pitchers were classified into the SD group (n=26) or the non-SD group (n=12). They were evaluated with the Kerlan-Jobe Orthopaedic Clinic shoulder and elbow (KJOC) scale and clinical measurements of shoulder characteristics, and with measurements of scapular kinematics, muscle activation, and ball speed during fastball pitching. Compared to the controls, the pitchers with SD had less scapular external rotation (difference=11.3 degrees, ES=0.92, p=0.012) during overall pitching and less upper trapezius (UT) activation during the late cocking (difference=7.1%, ES=0.79, p=0.019) and acceleration phases (difference=12.5%, ES=0.75, p=0.035). Higher UT activation during the late cocking phase was significantly associated with higher KJOC scores (standardized ß=0.415, p=0.039). In conclusion, deficits in scapular external rotation and decreased UT activation during pitching were found in pitchers with SD. Higher UT activation may be important for shoulder function in pitchers with SD.

Machine-learning-based detection of degenerative temporomandibular joint diseases using lateral cephalograms.

INTRODUCTION: Degenerative temporomandibular joint diseases (DJDs) are common diseases in dental practice, characterized by a series of degenerative processes in the temporomandibular joint. Early clinical detection of DJD by dental practitioners can be beneficial to prevent or alleviate the further progression of the disease. This study aimed to develop a cephalogram-based multidimensional nomogram to screen DJD. METHODS: A total of 502 patients (170 normal and 332 with DJD) were randomly assigned to a training set (n = 351) or a validation set (n = 151). Thirty-six cephalometric parameters were extracted from the cephalograms to be used as input for a predictive machine-learning algorithm. Multivariable logistic regression was used to construct a combined model for visualization in the form of a nomogram. Receiver operating characteristic curve, calibration testing, and decision curve analyses were conducted to evaluate the performance of the combined model. RESULTS: A Ceph score consisting of 22 cephalometric parameters were significantly associated with DJD (P <0.01). A combined model that consisted of Ceph scores and clinical features (including age, gender, limited mouth opening, crepitus, etc.) performed well in the receiver operating characteristic curve (area under the curve, 0.893), calibration test, and decision curve analyses, indicating its potential clinical value. CONCLUSIONS: This study constructed and verified a multidimensional nomogram consisting of Ceph scores and clinical features, which may contribute to the clinical screening of DJD in dental practice. Future studies are needed to test the reliability of the model with similar parameters.

Intramolecular Cyclization: A Convenient Strategy to Realize Efficient BT.2020 Blue Multi-Resonance Emitter for Organic Light-Emitting Diodes.

Rationally tuning the emission position and narrowing the full width at half-maximum (FWHM) of an emitter is of great importance for many applications. By synergistically improving rigidity, strengthening the resonant strength, inhibiting molecular bending and rocking, and destabilizing the HOMO energy level, a deep-blue emitter (CZ2CO) with a peak wavelength of 440 nm and an ultranarrow spectral FWHM of 16 nm (0.10 eV) was developed via intramolecular cyclization in a carbonyl/N resonant core (QAO). The dominant υ0-0 transition character of CZ2CO gives a Commission Internationale de I'Éclairage coordinates (CIE) of (0.144, 0.042), nicely complying with the BT.2020 standard. Moreover, a hyper-fluorescent device based on CZ2CO shows a high maximum external quantum efficiency (EQEmax ) of 25.6 % and maintains an EQE of 22.4 % at a practical brightness of 1000 cd m-2 .

Glenohumeral Internal Rotation Deficit on Pitching Biomechanics and Muscle Activity.

To characterize the scapular pitching biomechanics in symptomatic GIRD pitchers (SG) compared to asymptomatic GIRD (ASG) and healthy pitchers. The scapular kinematics and associated muscle activities during pitching were recorded in 33 high school pitchers. Compared to healthy, GIRD pitchers had less scapular posterior tilt in each pitching event (average difference, AD=14.4°, p<0.01) and ASG demonstrated less scapular upward rotation at ball release (AD=12.8°, p<0.01) and greater muscle activity in the triceps brachii in the early-cocking phase (AD=9.9%, p=0.015) and in the serratus anterior in the late-cocking phase (AD=30.8%, p<0.01). Additionally, SG had less muscular activity on triceps brachii in the acceleration phase and serratus anterior in the cocking phase (AD=37.8%, p=0.016; AD=15.5%, p<0.01, respectively) compared to ASG. GIRD pitchers exhibited less scapular posterior tilt during pitching, which may cause impingement. Since tightness of the anterior shoulder is a common cause of inadequacy of posterior tilt during arm elevation, stretching exercise of the anterior shoulder is recommended. Given the inadequate recruitment during pitching in the GIRD pitchers, symptoms may develop following potential impingement.

C-X-C motif chemokine ligand 1 and its receptor C-X-C motif chemokine receptor 2 in trigeminal ganglion contribute to nerve injury-induced orofacial mechanical allodynia.

BACKGROUND: Orofacial ectopic pain induced by trigeminal nerve injury is a serious complication of dental treatment. C-X-C motif chemokine ligand 1 (CXCL1) and its primary receptor C-X-C motif chemokine receptor 2 (CXCR2) contribute to the development and maintenance of neuropathic pain in the spinal nervous system, but their roles in trigeminal neuropathic sensation are still poorly understood. OBJECTIVES: This study aimed to investigate the exact role of CXCL1 and CXCR2 in the regulation of orofacial ectopic mechanical allodynia and their potential downstream mechanisms in the trigeminal ganglion (TG). METHODS: The head withdrawal threshold (HWT) of C57BL/6 mice was evaluated after inferior alveolar nerve (IAN) transection (IANX). Then, the distribution and expression of CXCL1 and CXCR2, and their potential downstream mechanisms in the TG were further measured using immunohistochemistry, real-time reverse transcription-quantitative polymerase chain reaction and Western blotting. Moreover, the effect of SB225002 (an inhibitor of CXCR2) on mechanical allodynia was examined. The data were analysed using the Student's t test and a analysis of variance (ANOVA). RESULTS: IANX triggered persistent (>21 days) mechanical allodynia and upregulation of CXCL1 and CXCR2 in the TG. In addition, exogenous CXCL1 also lowered the HWT, which was alleviated by CXCR2 and protein kinase C (PKC) antagonists (p < .05). In addition, IANX increased the phosphorylated PKC (p-PKC) levels and decreased the expression of voltage-gated potassium channels (Kv), and these effects were reversed by inhibition of CXCR2 (p < .05). CONCLUSION: Our results demonstrated that CXCR2 participated in orofacial ectopic mechanical allodynia via downregulation of Kv1.4 and Kv1.1 through the PKC signalling pathway. This mechanism may be a potential target in developing a treatment strategy for ectopic orofacial pain.

Activation of oxytocin receptor in the trigeminal ganglion attenuates orofacial ectopic pain attributed to inferior alveolar nerve injury.

This study explores the effects of oxytocin receptor (OXTR) in the trigeminal ganglion (TG) on orofacial neuropathic pain. We demonstrate that OXTR activation in the TG relieves the orofacial ectopic pain as well as inhibits the upregulated expression of calcitonin gene-related peptide (CGRP), IL-1ß, and TNFα in the TG and spinal trigeminal nucleus caudalis (SpVc) of rats with inferior alveolar nerve transection. OXTR, a G protein-coupled receptor, has been demonstrated to play a significant role in analgesia after activation by its canonical agonist oxytocin (OXT) in the dorsal root ganglion. However, the role of OXTR in the trigeminal nervous system on the orofacial neuropathic pain is still little known. In the present study, we aimed to investigate the regulation effect and mechanism of OXTR in the TG) and SpVc) on orofacial ectopic pain induced by trigeminal nerve injury. The inferior alveolar nerve (IAN) was transected to establish a ectopic pain model. A behavioral test with electronic von Frey filament demonstrated IAN transection (IANX) evoked mechanical hypersensitivity in the whisker pad from day 1 to at least day 14 after surgery. In addition, administration of OXT (50 and 100 µM) into the TG attenuated the mechanical hypersensitivity induced by IANX, which was reversed by pretreatment with L-368,899 (a selective antagonist of OXTR) into the TG. In addition, immunofluorescence showed the expression of OXTR in neurons in the TG and SpVc. Furthermore, Western blot analysis indicated that the upregulated expression of OXTR, CGRP, IL-1ß, and TNFα in the TG and SpVc after IANX was inhibited by the administration of OXT into the TG. And the inhibition effect of OXT on the expression of CGRP, IL-1ß, and TNFα was abolished by preapplication of OXTR antagonist L-368,899 into the TG.NEW & NOTEWORTHY This study explores the effects of oxytocin receptor (OXTR) in the trigeminal ganglion (TG) on orofacial neuropathic pain. We demonstrate that OXTR activation in the TG relieves the orofacial ectopic pain as well as inhibits the upregulated expression of calcitonin gene-related peptide, IL-1ß, and TNF-α in the TG and spinal trigeminal nucleus caudalis of rats with inferior alveolar nerve transection.

Comparison of the real-world effectiveness of vertical versus lateral functional hemispherotomy techniques for pediatric drug-resistant epilepsy: A post hoc analysis of the HOPS study.

OBJECTIVE: This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom. METHODS: We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method. RESULTS: Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique. SIGNIFICANCE: This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.

Hemispherectomy Outcome Prediction Scale: Development and validation of a seizure freedom prediction tool.

OBJECTIVE: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

Y06014 is a selective BET inhibitor for the treatment of prostate cancer.

Bromodomain and extra-terminal proteins (BETs) are potential targets for the therapeutic treatment of prostate cancer (PC). Herein, we report the design, the synthesis, and a structure-activity relationship study of 6-(3,5-dimethylisoxazol-4-yl)benzo[cd]indol-2(1H)-one derivative as novel selective BET inhibitors. One representative compound, 19 (Y06014), bound to BRD4(1) in the low micromolar range and demonstrated high selectivity for BRD4(1) over other non-BET bromodomain-containing proteins. This molecule also potently inhibited cell growth, colony formation, and mRNA expression of AR-regulated genes in PC cell lines. Y06014 also shows stronger activity than the second-generation antiandrogen enzalutamide. Y06014 may serve as a new small molecule probe for further validation of BET as a molecular target for PC drug development.

Physical activity and fitness in survivors of head and neck cancer.

PURPOSE: The purposes of the study were (1) to assess the physical activity (PA) status, muscle strength (MS), and flexibility of survivors of head and neck cancer (HNC) and compare these findings with normative data from national labor fitness measures; (2) to examine the differences among PA subgroups, as categorized using Godin's scores; and (3) to examine the association between stretching exercises and cervical range of motion (CROM). METHODS: A cross-sectional study with consecutive sampling was used to recruit HNC survivors from a medical center in Northern Taiwan who had completed either radiation therapy (RT) or multimodality treatments including RT within the current 5 years. The level of PA, daily function, fatigue, quality of life (QOL), MS (handgrip and hip flexor), BMI, and flexibility (CROM and fingertip-to-floor tests) of the participants were assessed. RESULTS: A total of 108 participants completed the assessments from 135 eligible patients (80% response rate). Although 60.2% reported engaging in PA, only 16.7% met WHO guidelines. Compared to subjects in the normative data, the survivors of HNC in this study had poorer handgrip strength, BMI, and CROM, but better forward flexion. The participants who were consistent with WHO PA guidelines reported less fatigue, better right hip flexor MS, and better QOL than those who did not engage in any PA. CONCLUSION: Lack of sufficient PA and generally poorer fitness were found in study subjects. Longitudinal research to explore changes in fitness and barriers to PA compliance is strongly suggested to better enhance HNC patients' PA and fitness.

Activation of the RAS/B-RAF-MEK-ERK pathway in satellite glial cells contributes to substance p-mediated orofacial pain.

The cross talk between trigeminal ganglion (TG) neurons and satellite glial cells (SGCs) is crucial for the regulation of inflammatory orofacial pain. Substance P (SP) plays an important role by activating neurokinin (NK)-I receptors in this cross talk. The activation of extracellular signal-regulated kinase (ERK) 1/2, protein kinase A (PKA) and protein kinase C (PKC) in neurons and SGCs of peripheral ganglions by peripheral inflammation is associated with inflammatory hypersensitivity. This study tested the hypothesis that SP evoked SP-NK-I receptor positive feedback via the Renin-Angiotensin System/B-Protein Kinase A-Rapidly Accelerates Fibrosarcoma-MEK-Extracellular Signal-Regulated Kinase (RAS/PKA-RAF-MEK-ERK) pathway, which is involved in pain hypersensitivity. Inflammatory models were induced in vivo by injecting Complete Freund's adjuvant (CFA) into the whisker pad of rats. SP was administrated to SGCs in vitro for investigating, whether SP regulates the expression of NK-I receptor in the SGC nucleus. The effects of RAS-RAF-MEK, PKA and PKC pathways in this process were measured by co-incubating SGCs with respective Raf, PKA, PKC and MEK inhibitors in vitro and by pre-injecting these inhibitors into the TG in vivo. SP significantly upregulated NK-I receptor, p-ERK1/2, Ras, B-Raf, PKA and PKC in SGCs under inflammatory conditions. In addition, L703,606 (NK-I receptor antagonist), U0126 (MEK inhibitor), Sorafenib (Raf inhibitor) and H892HCL (PKA inhibitor) but not chelerythrine chloride (PKC inhibitor) significantly decreased NK-I mRNA and protein levels induced by SP. The allodynia-related behavior evoked by CFA was inhibited by pre-injection of L703,606, U0126, Sorafenib and H892HCL into the TG. Overall, SP upregulates NK-I receptor in TG SGCs via PKA/RAS-RAF-MEK-ERK pathway activation, contributing to a positive feedback of SP-NK-I receptor in inflammatory orofacial pain.

Measurement of scapular prominence in symptomatic dyskinesis using a novel scapulometer: reliability and the relationship to shoulder dysfunction.

BACKGROUND: No previous studies have investigated whether the extent of scapular dyskinesis is associated with shoulder dysfunction. This study aimed (1) to establish the reliability of a scapulometer in patients with shoulder pain and (2) to investigate the related factors associated with shoulder dysfunction. METHODS: One hundred participants with symptomatic scapular dyskinesis were recruited. Twenty-one participants were involved in the reliability study to test the intrarater and inter-rater reliabilities of the scapulometer in patients with shoulder pain. After demographic data and self-reported Flexilevel Scale of Shoulder Function (FLEX-SF) scores were recorded, all participants were measured with a scapulometer to determine the posterior displacement of the root of the spine (ROS) and the inferior angle (IFA) of the scapula from the thorax. Next, the participants performed 5 trials of bilateral scapular plane elevation for scapular kinematics and electromyographic (EMG) data collection. Stepwise multiple linear regressions were used to determine the relationships between self-reported FLEX-SF scores and potential factors. In addition to scapular displacement, pain level, scapular kinematics, and EMG data were included as independent variables. RESULTS: The intrarater and inter-rater reliabilities of the scapulometer were excellent (intraclass correlation coefficient [ICC] = 0.93-0.97) and moderate to good (ICC = 0.74-0.81), respectively. The Bland-Altman plots showed no systematic bias between raters in the ROS and IFA measurements. Final stepwise multiple regression models showed that more ROS distance, higher serratus anterior activity, and lower pain level during arm elevation were associated with higher shoulder function (total R2 = 0.253). CONCLUSION: The reliability of the scapulometer in patients with shoulder pain is moderate to excellent. Scapular dyskinesis may be a compensatory strategy to avoid shoulder pain and improve shoulder function.

Oral Health-Related Quality of Life in Chinese Children With Orofacial Cleft.

OBJECTIVE: To measure the validity and reliability of a Chinese version of Child Oral Health Impact Profile (COHIP) and to assess oral health-related quality of life (OHRQoL) with regard to gender, age, and cleft types in Chinese children with orofacial cleft (OFC). DESIGN: A total of 120 patients with OFC (8-15 years old) and their parents were investigated with COHIP in the West China Hospital of Stomatology. Items were divided into oral symptoms, functional well-being, emotional well-being, school, and peer interaction subscales, and scores on all subscales were compared between and within groups. RESULTS: The internal consistency measured by Cronbach α was satisfactory in children's sample (0.85) and parents' sample (0.90). The correlation between children's and parents' questionnaires was moderate to weak (Pearson r = 0.34), which was also supported by moderate intraclass correlation coefficients. The OHRQoL of children differed significantly from parents on the overall COHIP, functional well-being, emotional well-being, and school subscales. Older children had poor OHRQoL, functional well-being, and emotional well-being. Girls had poor emotional well-being. Children with cleft lip and palate and cleft palate performed worse on the overall COHIP, functional well-being, and school subscales. Parents, boys, and younger children had better treatment expectations and global health perceptions. CONCLUSION: The Chinese version of COHIP is a reliable and valid tool to assess OHRQoL in Chinese children with OFC. Parents' reports could not replace children's answers but add complementary information. Children's gender, age, and cleft types should be considered in OHRQoL assessment and individual treatment plan.

P2Y14 receptor is functionally expressed in satellite glial cells and mediates interleukin-1ß and chemokine CCL2 secretion.

Satellite glial cells (SGCs) activation in the trigeminal ganglia (TG) is critical in various abnormal orofacial sensation in nerve injury and inflammatory conditions. SGCs express several subtypes of P2 purinergic receptors contributing to the initiation and maintenance of neuropathic pain. The P2Y14 receptor, a G-protein-coupled receptor activated by uridine diphosphate (UDP)-glucose and other UDP sugars, mediates various physiologic events such as immune, inflammation, and pain. However, the expression, distribution, and function of P2Y14 receptor in SGCs remains largely unexplored. Our study reported the expression and functional identification of P2Y14 receptor in SGCs. SGCs were isolated from TG of rat, and the P2Y14 receptor expression was examined using immunofluorescence technique. Cell proliferation and viability were examined via cell counting kit-8 experiment. Immunofluorescence demonstrated the presence of P2Y14 receptor in SGCs. Immunofluorescence and western blot showed that UDP-glucose treatment upregulated glial fibrillary acid protein, a common marker for glial activation. Extracellular UDP-glucose enhanced the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, which were both abolished by the P2Y14 receptor inhibitor (PPTN). Furthermore, quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay demonstrated that extracellular UDP-glucose significantly enhanced interleukin-1ß (IL-1ß) and chemokine CCL2 (CCL2) release, which was abolished by PPTN and significantly decreased by inhibitors of MEK/ERK (U0126) and p38 (SB202190). Our findings directly proved the functional presence of P2Y14 receptor in SGCs. It was also verified that P2Y14 receptor activation was involved in activating SGCs, phosphorylating MAPKs, and promoting the secretion of IL-1ß and CCL2 via ERK and p38 pathway.