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Post-traumatic stress disorder (PTSD) is a psychiatric disease that seriously affects brain function. Currently, selective serotonin reuptake inhibitors (SSRIs) are used to treat PTSD clinically but have decreased efficiency and increased side effects. In this study, nasal cannabidiol inclusion complex temperature-sensitive hydrogels (CBD TSGs) were prepared and evaluated to treat PTSD. Mice model of PTSD was established with conditional fear box. CBD TSGs could significantly improve the spontaneous behavior, exploratory spirit and alleviate tension in open field box, relieve anxiety and tension in elevated plus maze, and reduce the freezing time. Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex, amygdala, and hippocampus CA1. CBD TSGs could reduce the level of tumor necrosis factor-α caused by PTSD. Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1A receptor. Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration, as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs. Overall, nasal CBD TSGs are safe and effective and have controlled release. There are a novel promising option for the clinical treatment of PTSD., Graphical abstract Nasal delivery of cannabidiol inclusion complex temperature-sensitive hydrogels could effectively target to brains for the treatment of mice with post-traumatic stress disorder (PTSD), which is a novel promising option for the clinical treatment of PTSD.Image 1

Introduction Metastasis is the primary cause of lung cancer-related death. Nevertheless, the underlying molecular mechanisms and evolutionary patterns of lung cancer metastases are still elusive. Methods We performed whole-exome sequencing for 40 primary tumors (PTs) and 61 metastases from 47 patients with lung cancer, of which 40 patients had paired PTs and metastases. The PT-metastasis genomic divergence, metastatic drivers, timing of metastatic dissemination, and evolutionary origins were analyzed using appropriate statistical tools and mathematical models. Results There were various degrees of genomic heterogeneity when comparing the paired primary and metastatic lesions or comparing metastases of different sites. Multiple metastasis-selected/enriched genetic alterations were found, such as MYC amplification, NKX2-1 amplification, RICTOR amplification, arm 20p gain, and arm 11p loss, and these results were were also featured in a meta-analysis cross-validated using an independent cohort from Memorial Sloan-Kettering Cancer Center database. To elucidate the metastatic seeding time, we applied a metastatic model and found 61.1% of the tumors were late dissemination, in which the metastatic seeding happened approximately 2.74 years before clinical detection. One exception was lymph node metastases whose dissemination time was relatively early. By analyzing the evolutionary origins, we reported that nonlymph node metastases were mainly seeded by the PT (87.5%) rather than the earlier colonized lymph node metastases. Conclusions Our results shed light on the molecular features that potentially drive lung cancer metastases. The distinct temporospatial pattern of disease progression revealed that lung cancer was susceptible to either late dissemination or indolent early lymph node metastases, leaving a potential time window to minimize metastases by early cancer detection.

To estimate the prevalence of primary immune thrombocytopenia (ITP) and describe ITP-associated healthcare resource utilization (HRU) among Texas Medicaid beneficiaries.A retrospective analysis using 2012-2015 Texas Medicaid claims data was conducted to estimate the annual prevalence of ITP. HRU was summarized for the 12-month period following initial ITP diagnosis. Logistic regression and generalized linear model were used to investigate predictors for all-cause and ITP-related HRU.The average annual prevalence of ITP was 17.0 per 100,000 persons; higher among females vs males (17.4 vs 13.6 per 100,000) and highest among adults aged ≥ 65 years (36.7 per 100,000). Among 325 patients included in the HRU analyses, 49.2% received ITP therapies. More than half of patients had at least one all-cause emergency department (ED) visit (70.5%) and/or hospitalization (56.0%). One-third (32.6%) experienced at least one ITP-related ED visit and 40.3% had at least one ITP-related hospitalization. Compared to adults aged 18-49 with ITP, children aged 0-4 (odds ratio [OR] = 3.65,There are 17 patients diagnosed with ITP for every 100,000 Texas Medicaid enrollees annually, with higher prevalence in females and the elderly. Children are more likely to experience hospitalizations and ED visits associated with ITP. ITP patients in Texas Medicaid utilize more healthcare resources compared to the general Medicaid population.

Summary Background & aims To date, the prevalence of Gestational diabetes mellitus (GDM) in China was 17.5%. Given the substantial relevance of GDM for medium- and long-term health of both mother and offspring and the paucity of existing data on the link between maternal diet and glucose homeostasis during pregnancy in Asian population, additional studies are needed. To examine the relevance of dietary glycemic index (GI), glycemic load (GL) and fiber intake before and during pregnancy for the development of GDM and glucose homeostasis over the course of pregnancy. Methods Cox proportional hazards analysis and linear mixed effects regressions were performed on data from 9317 women for whom three food frequency questionnaires (pre-pregnancy, 1st and 2nd trimesters) and biochemical measures during pregnancy were available. Investigated outcome variables included GDM risk, fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), and homeostasis model assessment insulin resistance (HOMA-IR) in the 1st, 2nd and 3rd trimesters. Results Women in the highest tertile of dietary GI (or GL) before pregnancy, in the 1st, or the 2nd trimester respectively had a 12% (15%), 25% (23%) or 29% (25%) higher risk of developing GDM than those in the lowest tertile (all p for trend ≤ 0.02). Women with the highest dietary fiber intake before pregnancy, in the 1st or 2nd trimester had a 11%, 17% or 18% lower GDM risk (all p for trend ≤ 0.03). Moreover, increases in GI or GL and decreases in fiber intake over the course of pregnancy (1st to 3rd trimesters) were independently associated with adverse concurrent developments in FPG, HbA1C and HOMA-IR (p ≤ 0.03). Conclusions Our study indicates that dietary GI, GL and fiber intake before and during pregnancy affects glucose homeostasis of pregnant Chinese women.

Yang Liu,1,* Feng-Jiao Zhang,2,* Xi-Xi Zhao,3,* Yuan Yang,4 Chun-Yi Liang,3 Li-Li Feng,5 Xiang-Bo Wan,5 Yi Ding,1 Yao-Wei Zhang1 1Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 2Shanghai Concord Medical Cancer Center, Shanghai, 200001, People’s Republic of China; 3Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Medical Image Processing, School of Biomedical Engineering, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 5Department of Radiation Oncology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Ding; Yao-Wei Zhang Tel +86 20-62786616Email dingyi197980@126.com; weiyaozhang2@163.comPurpose: Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for locally advanced rectal cancer (LARC). However, the accuracy of traditional clinical indicators in predicting tumor response is poor. Recently, radiomics based on magnetic resonance imaging (MRI) has been regarded as a promising noninvasive assessment method. The present study was conducted to develop a model to predict the pathological response by analyzing the quantitative features of MRI and clinical risk factors, which might predict the therapeutic effects in patients with LARC as accurately as possible before treatment.Patients and Methods: A total of 82 patients with LARC were enrolled as the training cohort and internal validation cohort. The pre-CRT MRI after pretreatment was acquired to extract texture features, which was finally selected through the minimum redundancy maximum relevance (mRMR) algorithm. A support vector machine (SVM) was used as a classifier to classify different tumor responses. A joint radiomics model combined with clinical risk factors was then developed and evaluated by receiver operating characteristic (ROC) curves. External validation was performed with 107 patients from another center to evaluate the applicability of the model.Results: Twenty top image texture features were extracted from 6192 extracted-radiomic features. The radiomics model based on high-spatial-resolution T2-weighted imaging (HR-T2WI) and contrast-enhanced T1-weighted imaging (T1+C) demonstrated an area under the curve (AUC) of 0.8910 (0.8114– 0.9706) and 0.8938 (0.8084– 0.9792), respectively. The AUC value rose to 0.9371 (0.8751– 0.9997) and 0.9113 (0.8449– 0.9776), respectively, when the circumferential resection margin (CRM) and carbohydrate antigen 19-9 (CA19-9) levels were incorporated. Clinical usefulness was confirmed in an external validation cohort as well (AUC, 0.6413 and 0.6818).Conclusion: Our study indicated that the joint radiomics prediction model combined with clinical risk factors showed good predictive ability regarding the treatment response of tumors as accurately as possible before treatment.Keywords: rectal cancer, neoadjuvant chemoradiotherapy, magnetic resonance imaging, tumor response

A 60‐year‐old man was hospitalized because of numbness and weakness in the right upper limb. Magnetic resonance imaging revealed a large mass in the right upper lobe invading the right eighth cervical and first thoracic nerve root. Biopsy pathology confirmed primary lung adenocarcinoma with a clinical stage of cT4N0M0 IIIA, negative for anaplastic lymphoma kinase fusion gene and epidermal growth factor receptor mutations but positive for programmed death ligand 1 (3%). Neoadjuvant tislelizumab and chemotherapy were offered to this patient with Pancoast tumor, and tumor shrinkage of 71% was achieved. After the operation, surgical pathology indicated pathologic complete response (pCR). Circulating tumor cells testing was negative after the first adjuvant treatment. In this case, we provide real‐world evidence of encouraging pCR with neoadjuvant tislelizumab and chemotherapy for a patient with Pancoast tumor., • Neoadjuvant tislelizumab and chemotherapy was offered for a patient with Pancoast tumor (TNM stage, cT4N0M0 IIIA). • Surgical resection was successfully performed and a pCR was achieved.

Interleukin (IL)-17 and its related cytokines have been shown to be involved in myocardial fibrosis and irreversible ventricular remodelling, which have predictive values in the development of left ventricular diastolic dysfunction (LVDD). This study aimed to assess the correlation between IL-17 and LVDD, and investigate the prognostic value of IL-17 among patients with normal left ventricular ejection fraction (LVEF).A total of 120 patients with normal LVEF underwent left ventricular (LV) catheterisation for LV end-diastolic pressure (LVEDP) measurement and routine echocardiography. The follow-up period was 30 (18, 35) months.The levels of IL-17 and IL-6 from the systemic blood were significantly increased in non-heart failure (HF) patients with LVDD (p0.001). Receiver operating characteristic (ROC) revealed that the combination of IL-17 and IL-6 showed the highest diagnostic accuracy in predicting LVDD (AUC, 0.890; 95% CI, 0.835-0.945; p0.001), and the cut-off value was 41.5 pg/mL. On logistic regression analysis, the increment of the combination of IL-17 and IL-6 was an independent predictor for the prognosis of LVDD (odds ratio, 1.25; 95% CI, 1.01-1.12; p0.05). According to the cut-off value of the combination of IL-17 and IL-6, the patients with lower levels of IL-17 and IL-6 (41.5 pg/mL group) had a better prognosis. The increased levels of IL17 and IL-6 were significantly correlated with the levels of fibrotic parameters.Assessment of LVDD by measuring the combination of IL-17 and IL-6 might provide valuable prognostic significance for non-HF patients with LVDD.

Purpose: Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance. Experimental Design: We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. Results: ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased. Conclusions: Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.

The faithful execution of molecular programme underlying oocyte maturation and meiosis is vital to generate competent haploid gametes for efficient mammalian reproduction. However, the organization and principle of molecular circuits and modules for oocyte meiosis remain obscure. Here, we employed the recently developed single-cell RNA-seq technique to profile the transcriptomes of germinal vesicle (GV) and metaphase II (MII) oocytes, aiming to discover the dynamic changes of mRNAs and long non-coding RNAs (lncRNAs) during oocyte in vitro meiotic maturation. During the transition from GV to MII, total number of detected RNAs (mRNAs and lncRNAs) in oocytes decreased. Moreover, 1,807 (602 up- and 1,205 down-regulated) mRNAs and 313 (177 up- and 136 down-regulated) lncRNAs were significantly differentially expressed (DE), i.e., more mRNAs down-regulated, but more lncRNAs up-regulated. During maturation of pig oocytes, mitochondrial mRNAs were actively transcribed, eight of which (ND6, ND5, CYTB, ND1, ND2, COX1, COX2 and COX3) were significantly up-regulated. Both DE mRNAs and targets of DE lncRNAs were enriched in multiple biological and signal pathways potentially associated with oocyte meiosis. Highly abundantly expressed mRNAs (including DNMT1, UHRF2, PCNA, ARMC1, BTG4, ASNS and SEP11) and lncRNAs were also discovered. Weighted gene co-expression network analysis (WGCNA) revealed 20 hub mRNAs in three modules to be important for oocyte meiosis and maturation. Taken together, our findings provide insights and resources for further functional investigation of mRNAs/lncRNAs in in vitro meiotic maturation of pig oocytes.

The diagnosis and treatment of massive hemoptysis remain challenging. We report a 28-year-old woman with refractory massive hemoptysis caused by a mediastinal hemangioma. Despite multiple bronchial artery embolizations and fiberoptic bronchoscopy treatments, effective control of the bleeding and clearing of the airway was not possible. Finally, with the support of venovenous extracorporeal membrane oxygenation, mediastinal hemangioma resection and right upper lobe sleeve resection were simultaneously performed. During the operation, many blood clots in the airway were removed. The airway bleeding was effectively controlled, and the patient recovered.

Little research has examined burn injury in the pediatric population with autism spectrum disorder (ASD). We used data from Taiwan’s National Health Insurance Research Database to identify 15,844 participants aged

Peripheral inflammation and nerve injury usually accompany each other. However, whether inflammatory and neuropathic pain share similar mechanisms at all stages is unknown. TRPV1 and P2X3 are two major ion channels in dorsal root ganglia (DRGs) and are involved in chronic pain. Here, their function and expression in DRGs at different phases of the two types of pain were investigated. Both the paw withdrawal threshold (PWT) and paw withdrawal latency were decreased in rats injected with complete Freud's adjuvant (CFA). However, only the PWT was decreased in rats with spared nerve injury (SNI). CFA increased the magnitude of the TRPV1-mediated Ca2+ response but not the P2X3-mediated Ca2+ response 14 days after injection. Consistent with this result, the P2X3 expression level in CFA rats was increased only at 3 days after injection. SNI surgery increased the magnitudes of the TRPV1- and P2X3-mediated Ca2+ responses and upregulated both TRPV1 and P2X3 expression in lumbar DRGs. The distributions of TRPV1 and P2X3 in DRGs after modeling were observed, and TRPV1 was found to be highly expressed mainly in the L4-L5 DRGs in CFA rats and in the L5-L6 DRGs in SNI rats. P2X3 was highly expressed in the L4-L6 DRGs in CFA rats 3 days after injection but was only highly expressed in the L4 DRG 14 days after modeling. On the other hand, SNI promoted the P2X3 expression L4-L5 DRGs 3 days after surgery, but only L6 DRG 14 days after modeling. All the results indicate that P2X3 and TPRV1 are involved in inflammatory and neuropathic pain by different expression levels and distributions in the lumbar DRG in the chronic stage.

This study reveals an uncovered mechanism for the regulation of polyamine homeostasis through protein arginyl citrullination of antizyme (AZ), a natural inhibitor of ornithine decarboxylase (ODC). ODC is critical for the cellular production of polyamines. AZ binds to ODC dimers and promotes the degradation of ODC via the 26S proteasome. This study demonstrates the protein citrullination of AZ catalyzed by peptidylarginine deiminase type 4 (PAD4) both in vitro and in cells. Upon PAD4 activation, the AZ protein was citrullinated and accumulated, leading to higher levels of ODC proteins in the cell. In the PAD4-overexpressing and activating cells, the levels of ODC enzyme activity and the product putrescine increased with the level of citrullinated AZ proteins and PAD4 activity. Suppressing cellular PAD4 activity reduces the cellular levels of ODC and downregulates cellular polyamines. Furthermore, citrullination of AZ in the C-terminus attenuates AZ function in the inhibition, binding, and degradation of ODC. This paper provides evidence to illustrate that PAD4-mediated AZ citrullination upregulates cellular ODC and polyamines by retarding ODC degradation, thus interfering with the homeostasis of cellular polyamines, which may be an important pathway regulating AZ functions that is relevant to cancer biology.

Amyotrophic lateral sclerosis (ALS) was initially thought to be associated with oxidative stress when it was first linked to mutant superoxide dismutase 1 (SOD1). The subsequent discovery of ALS-linked genes functioning in RNA processing and proteostasis raised the question of how different biological pathways converge to cause the disease. Both familial and sporadic ALS are characterized by the aggregation of the essential DNA- and RNA-binding protein TDP-43, suggesting a central role in ALS etiology. Here we report that TDP-43 aggregation in neuronal cells of mouse and human origin causes sensitivity to oxidative stress. Aggregated TDP-43 sequesters specific microRNAs (miRNAs) and proteins, leading to increased levels of some proteins while functionally depleting others. Many of those functionally perturbed gene products are nuclear-genome-encoded mitochondrial proteins, and their dysregulation causes a global mitochondrial imbalance that augments oxidative stress. We propose that this stress-aggregation cycle may underlie ALS onset and progression.

Drug refractory epilepsy (RE) is believed to be associated with structural lesions, but some RE patients show no significant structural abnormalities (RE-no-SA) on conventional magnetic resonance imaging scans. Since most of the medically controlled epilepsy (MCE) patients also do not exhibit structural abnormalities, a reliable assessment needs to be developed to differentiate RE-no-SA patients and MCE patients to avoid misdiagnosis and inappropriate treatment. Using resting-state scalp electroencephalogram (EEG) datasets, we extracted the spatial pattern of network (SPN) features from the functional and effective EEG networks of both RE-no-SA patients and MCE patients. Compared to the performance of traditional resting-state EEG network properties, the SPN features exhibited remarkable superiority in classifying these two groups of epilepsy patients, and accuracy values of 90.00% and 80.00% were obtained for the SPN features of the functional and effective EEG networks, respectively. By further fusing the SPN features of functional and effective networks, we demonstrated that the highest accuracy value of 96.67% could be reached, with a sensitivity of 100% and specificity of 92.86%. Overall, these findings not only indicate that the fused functional and effective SPN features are promising as reliable measurements for distinguishing RE-no-SA patients and MCE patients but also may provide a new perspective to explore the complex neurophysiology of refractory epilepsy.

Objectives Hypoxia is one of the characteristics of microenvironmental changes after orthognathic surgery for fractures. HIF-1α is a main regulator of the hypoxic response and plays a crucial role in bone formation, remodelling, and homeostasis. Osteoclasts participate in bone absorption and affect osteogenesis, and osteoclasts differentiate in a path from the oxygen-rich bone marrow to oxygen-deficient bone lesions. Thus, we aimed to study the key functions of HIF-1α in osteoclasts during mandibular healing after osteotomy. Materials and methods The function of HIF-1α in osteoclasts during fracture healing in osteoclast-specific HIF-1α-conditional-knockout mice was investigated in mandibular osteotomy. Primary osteoclasts were used to explore the expression of HIF-1α and cardiotrophin-1 (CT-1) at both the mRNA and protein levels. The ability of BMSCs co-cultured with conditioned media from osteoclast-specific HIF-1α-knockout primary osteoclasts was detected using osteoclast-mediated osteogenesis experiments. Results Hypoxia-inducible factor-1α increased osteoclastogenesis and bone resorption, and a delay in bone healing was found in osteoclast-specific HIF-1α-conditional-knockout mice compared with normal mice. HIF-1α-knockout primary osteoclasts inhibited bone resorption and CT-1 expression, and HIF-1α enhanced the osteoclast-mediated stimulation of BMSC differentiation by secreting CT-1. Conclusions Hypoxia-inducible factor-1α can play a key role in the physiology and pathogenesis of bone resorption by promoting osteoclastogenesis during fracture and influencing osteogenesis through CT-1 during bone healing.

Signaling pathways and transcription factors are involved in porcine embryonic development. Here, we demonstrate that glycogen synthase kinase-3 (GSK3) inhibitor, CHIR99021 and recombinant porcine interleukin-6 (rpIL6) significantly promote porcine parthenogenetic blastocyst formation (49.23 ± 8.40% vs 32.34 ± 4.15%), with increased inner cell mass (ICM) cell numbers (7.72 ± 2.30 vs 4.28 ± 1.60) and higher expression of pluripotent genes, such as OCT4, SOX2 and NANOG. Furthermore, CHIR99021 and rpIL6 improve blastocyst quality with increased blastocyst hatching percentage (16.19 ± 1.96% vs 10.25 ± 1.12%) and subsequently porcine pluripotent stem cells (pPSCs) derivation efficiency. These results advance the understanding of porcine pre-implantation development and provide evidences in improving the blastocyst quality.

We identified FLY as a previously uncharacterized RNA-binding-family protein that controls flowering time by positively regulating the expression of FLC clade members. The ability of flowering plants to adjust the timing of the floral transition based on endogenous and environmental signals contributes to their adaptive success. In Arabidopsis thaliana, the MADS-domain protein FLOWERING LOCUS C (FLC) and the FLC clade members FLOWERING LOCUS M/MADS AFFECTING FLOWERING1 (FLM/MAF1), MAF2, MAF3, MAF4, and MAF5 form nuclear complexes that repress flowering under noninductive conditions. However, how FLM/MAF genes are regulated requires further study. Using a genetic strategy, we showed that the previously uncharacterized K-homology (KH) domain protein FLOWERING LOCUS Y (FLY) modulates flowering time. The fly-1 knockout mutant and FLY artificial microRNA knockdown line flowered earlier than the wild type under long- and short-day conditions. The knockout fly-1 allele, a SALK T-DNA insertion mutant, contains an ~ 110-kb genomic deletion induced by T-DNA integration. FLC clade members were downregulated in the fly-1 mutants and FLY artificial microRNA knockdown line, whereas the level of the FLC antisense transcript COOLAIR was similar to that of the wild type. Our results identify FLY as a regulator that affects flowering time through upregulation of FLC clade members.

Complex regional pain syndrome (CRPS) results in chronic and excruciating pain in patients. Conventional therapies lack effectiveness, rendering it one of the most difficult to treat neurological conditions.. Electroacupuncture (EA) is an effective alternative therapy for pain relief. Here, we investigated whether EA exerts analgesic effect on a rat model of CRPS type-I (CRPS-I) and related mechanisms. The rat chronic postischemic pain (CPIP) model was established to mimic CRPS-I. 100Hz EA exerted robust and persistent antiallodynic effect on CPIP model compared with 2 Hz EA or sham EA. EA markedly suppressed the overexpression of CXCL12/CXCR4 in spinal cord dorsal horn (SCDH) of CPIP model, leading to substantial decrease in neuronal and glial cell activities in SCDH. Pharmacological blocking CXCR4 mimicked EA-induced antiallodynic effect and related cellular events in SCDH, whereas exogenous CXCL12 abolished EA's effect. CXCR4 signaling resulted in ERK activation in SCDH, contributing to mechanical allodynia of CPIP model rats, whereas EA markedly reduced ERK activation. Therefore, we demonstrated that EA interferes with CXCL12/CXCR4 signaling in SCDH and downstream ERK pathway to exert robust antiallodynic effect on an animal model of CRPS-I. Our work suggests that EA may be a potential therapeutic option for CRPS-I in clinic. PERSPECTIVE: Our work identified that EA exerts robust antiallodynic effect on an animal model of CRPS-I, via mechanisms involving inhibition of CXCL12/CXCR4 signaling. EA further attenuates downstream neuronal and glial cell activation and ERK pathway in SCDH. This work suggests that EA may be a potential therapeutic option for CRPS-I management in clinic.

FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor1-4, but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2)5,6, but also acts as a steroid hormone receptor coactivator through mechanisms that are unclear. Here we show, in prostate cancer cells, that LSD1 associates with FOXA1 and active enhancer markers, and that LSD1 inhibition globally disrupts FOXA1 chromatin binding. Mechanistically, we demonstrate that LSD1 positively regulates FOXA1 binding by demethylating lysine 270, adjacent to the wing2 region of the FOXA1 DNA-binding domain. Acting through FOXA1, LSD1 inhibition broadly disrupted androgen-receptor binding and its transcriptional output, and dramatically decreased prostate cancer growth alone and in synergy with androgen-receptor antagonist treatment in vivo. These mechanistic insights suggest new therapeutic strategies in steroid-driven cancers.

Furan, which has been identified as possibly carcinogenic for humans, can be induced to different food items by thermal treatment. In accordance with the previous studies and risks associated with prevalence of furan in food, it is necessary to be acknowledged of amounts of furan formed in different thermally processed foods for human awareness. In this study, Headspace Solid-Phase Microextraction Gas Chromatography–Mass Spectrometry (HS-SPME-GC/MS) was optimized for simultaneous determination of furan, furfural, 2-methylfuran and 2-pentylfuran for the first time from different dried fruits and roasted nuts. The method was proved to be valid for determination of all analytes at 50 °C for 25 min, stirring at 700 rpm and 20% NaCl (W/V) using 50/30 μm divinlybenzene/carboxen/polysimethylsiloxane (DVB/CAR/PDMS) fibre. All analytes were baseline-separated at HP 5-MS column in less than 13 min and obtained results have shown prevalence of furan, furfural and 2-pentylfuran in the studied matrices; however, 2-pentylfuran was more prevalent in the roasted nuts than dried fruits and 2-methylfuran has not shown considerable prevalence in both matrices. Moreover, this method was validated in terms of linearity, precision, recovery, specificity, limit of detection and limit of quantification depending on analytes and sample matrices. Hence, the present method was proved to be highly sensitive, specific and robust with good precision and accuracy and suitable for monitoring these furan derivatives in the studied matrices.

People who find meaning in life can endure 'any' pain. However, there were no tools to investigate elderly individuals' sources of meaning in life in China. This study aimed to develop the Sources of Meaning in Life Scale for the Elderly (SMSE), and examine the validation and reliability in Chinese elderly.A 43-item pool of SMSE was formed by combining the preliminary interview and literature review. A cross-sectional survey of 627 elderly people was then conducted in two community health service centers, two hospitals, and two nursing homes in Guangzhou by the convenience sampling method. Test-retest reliability was assessed with 24 elderly persons.Six dimensions, containing family (four items), social support (four items), value (seven items), life security (four items), personal development (four items), and leisure activity (five items) explained 62.16% of the variance in total. Confirmatory factor analysis model fitting indices were χThe SMSE has good reliability and validity that can be used to evaluate the sources of meaning and meaning in life for the elderly.

Objective: This study examined preschoolers with teacher-reported or parent-reported situational hyperactivity, and whether they differed in terms of behavioral problems, attentional problems, and parenting perceptions. Method: We used the Conners’ Kiddie Continuous Performance Test and the Color Flanker Task to assess 99 preschoolers with pervasive high-ADHD-symptoms (42), school-situational high-ADHD-symptoms (30), or home-situational high-ADHD-symptoms (27), plus 111 preschoolers with pervasive low-ADHD-symptoms. Parents and teachers reported externalizing/internalizing behavioral problems. Parenting perceptions were measured with the Parenting Stress Index-Short Form and a parenting perceptions scale. Results: Preschoolers with school-situational high-ADHD-symptoms had deficits in attentional control. Parents of preschoolers with home-situational high-ADHD-symptoms had higher levels of parental stress and perceived their parenting to be harsher. Preschoolers with pervasive high-ADHD-symptoms had deficits in attentional control, increased parental stress, and parents with harsher parenting perceptions. Conclusion: Preschoolers with situational high-ADHD-symptoms may have different contextual risk factors related to ADHD symptoms reported by parents versus teachers.

Background and objectives Patients with femoral neck fractures often suffer severe pain. This randomized controlled clinical study compared the effect of femoral nerve block (FNB) and fascia iliaca compartment block (FICB) in this population. Patients and methods Forty-six patients were randomly assigned to one of the two groups: FNB group (femoral nerve block, n=23) or FICB group (fascia iliaca compartment block, n=23). Before positioning for spinal anesthesia, patients received FNB with 15 mL of 0.5% ropivacaine or FICB with 40 mL of 0.5% ropivacaine. Pain was evaluated using a visual analogue scale (VAS) at rest and during hip flexion after admission to the operation room; at 3, 5, 8, and 10 min after analgesia intervention; and during positioning for spinal anesthesia. Positioning was attempted after 10 min of analgesia intervention in each group. Time required to perform spinal anesthesia, quality of positioning, and patient satisfaction were documented. Results The VAS scores in the FNB group were significantly lower than those in FICB group at 3 and 5 min after analgesia intervention (P=0.000). However, there were no significant differences in VAS between groups at 8 or 10 min or during positioning. Conclusion FNB and FICB produce similar analgesic effects in patients with femoral neck fractures, but FNB has a more rapid onset of pain relief.

Background Small supernumerary marker chromosomes (sSMCs), are additional abnormal chromosomes, which can’t be detected accurately by banding cytogenetic analysis. Abnormal phenotypes were observed in about 30% of SMC carriers. Duplication of chromosome 15 and related disorders, characterized by hypotonia motor delays, autism spectrum disorder (ASD), intellectual disability, and epilepsy including infantile spasms, might be account for 50% of the total sSMCs. Case presentation An 11-month-old infant with an sSMC found by banding cytogenetics was referred to our clinic because of developmental retardation and autism spectrum disorder. After several months of rehabilitation treatment, the progress of motor development was obvious, but the consciousness was still far from satisfied. High-resolution karyotype analysis, multiplex ligation-dependent probe amplification and copy number variation sequencing (CNV-Seq) were conducted to confirm the identity of the sSMC. A bisatellited dicentric sSMC was observed clearly in high-resolution karyotype analysis and a 10.16-Mb duplication of 15q11.1q13.2 (3.96 copies) together with a 1.84-Mb duplication of 15q13.2q13.3 (3 copies) was showed by CNV-Seq in the proband. It suggested that the molecular cytogenetic karyotype was 47,XY,+dic(15;15)(q13.2;q13.3). Furthermore, the clinical symptoms of the proband mostly fit 15q duplication related disorders which are characterized by hypotonia motor delays, autism spectrum disorder (ASD), and intellectual disability. Conclusion We reported for the first time using CNV-Seq to detect sSMCs and find a partial trisomy and tetrasomy of 15q11-q13 associated with developmental delay and autism spectrum disorder. Our report indicates that CNV-seq is a useful and economical way for diagnosis of dup15q and related disorders.

BackgroundModerate-to-severe postoperative pain following craniotomy has a high incidence in pediatric patients. Such pain may cause agitation, intracranial hypertension, epileptic seizures, and postoperative hematoma, which affect morbidity and mortality. Although scalp nerve block (SNB) achieves satisfactory pain relief except for suboccipital mid-craniotomy in adults and ropivacaine is widely used as a long-acting peripheral nerve block agent in children, there are few studies of SNB with ropivacaine in pediatric patients undergoing craniotomy. In addition, the neurosurgery operation time is relatively long, but the duration of action of SNB is limited. It is generally believed that postoperative SNB is better than preoperative SNB for postoperative analgesia. However, considering the concept of preemptive analgesia, we believe that preoperative SNB may achieve a longer postoperative analgesia effect than we expected.MethodsThis trial is a single-institution, prospective, randomized, controlled, double-blind study. A total of 180 children aged between 1 and 12 years who are undergoing elective craniotomy will be randomly allocated in a 1:1:1 ratio to three groups: group B (preoperative ropivacaine block group), group A (postoperative ropivacaine block group), and group N (nonblocking control group). This randomization will be stratified by age in two strata (1–6 years and 7–12 years). The primary outcome is the total consumption of sufentanil within 24 h after surgery. The secondary outcomes include assessment of pain scores, total consumption of sufentanil and emergency-remedy medicine consumption at observation points, the occurrence of postoperative complications, and the length of hospitalization after surgery.DiscussionThis study is designed to explore the effect and feasibility of SNB with ropivacaine for postoperative analgesia in pediatric patients undergoing craniotomy. Further aims are to compare the effects of preoperative and postoperative SNB on postoperative analgesia in order to identify whether there is a preemptive analgesic effect and determine the better time to implement SNB in pediatric patients during craniotomy.Trial registrationChinese Clinical Trial RegistryChiCTR1800017386. Registered on 27 July 2018.

Prion diseases are caused by the misfolding of prion protein (PrP). Misfolded PrP forms protease-resistant aggregates in vivo (PrPSc) that are able to template the conversion of the native form of the protein (PrPC), a property shared by in vitro–produced PrP fibrils. Here we produced amyloid fibrils in vitro from recombinant, full-length human PrPC (residues 23–231) and determined their structure using cryo-EM, building a model for the fibril core comprising residues 170−229. The PrP fibril consists of two protofibrils intertwined in a left-handed helix. Lys194 and Glu196 from opposing subunits form salt bridges, creating a hydrophilic cavity at the interface of the two protofibrils. By comparison with the structure of PrPC, we propose that two α-helices in the C-terminal domain of PrPC are converted into β-strands stabilized by a disulfide bond in the PrP fibril. Our data suggest that different PrP mutations may play distinct roles in modulating the conformational conversion. A cryo-EM structure of amyloid fibrils formed in vitro with recombinant human PrP provides insights into fibril architecture and the potential role of disease mutations.

Background Acute pain can transition to chronic pain, presenting a major clinical challenge. Electroacupuncture (EA) can partly prevent the transition from acute to chronic pain. However, little is known about the mechanisms underlying the effect of EA. This study investigated the effect of EA on pain transition and the activation of metabotropic glutamate receptor 5 (mGluR5)-protein kinase C epsilon (PKCe) signaling pathway in the dorsal root ganglia (DRG). Methods The hyperalgesic priming model was established by the sequential intraplantar injection of carrageenan (1%, 100 μL) and prostaglandin E2 (PGE2) into the left hind paw of rats. EA treatment (2/100 Hz, 30 min, once/day) was applied at bilateral Zusanli (ST36) and Kunlun (BL60) acupoints in rats. Von Frey filaments were used to investigate the mechanical withdrawal threshold (MWT) at different time points. The protein expression levels of mGluR5 and PKCe in the ipsilateral L4-L6 DRGs of rats were detected by Western blot. Some pharmacological experiments were performed to evaluate the relationship between mGluR5, PKCe and the MWT. It was also used to test the effects of EA on the expression levels of mGluR5 and PKCe and changes in the MWT. Results Sequential injection of carrageenan and PGE2 significantly decreased the MWT of rats and up-regulated the expression level of mGluR5 and PKCe in the ipsilateral L4-L6 DRGs. EA can reverse the hyperalgesic priming induced by sequential injection of carrageenan/PGE and down-regulate the protein expression of mGluR5 and PKCe. Glutamate injection instead of PGE2 can mimic the hyperalgesic priming model. Pharmacological blocking of mGluR5 with specific antagonist MTEP can prevent the hyperalgesic priming and inhibit the activation of PKCe in DRGs. Furthermore, EA also produced analgesic effect on the hyperalgesic priming rats induced by carrageenan/mGluR5 injection and inhibited the high expression of PKCe. Sham EA produced none analgesic and regulatory effect. Conclusion EA can regulate pain transition and it may relate with its inhibitory effect on the activation of mGluR5-PKCe signaling pathway in the DRGs.

Corticosteroid insensitivity is a feature of airway inflammation in chronic obstructive pulmonary disease (COPD). Erythromycin exhibits anti-inflammatory activity in COPD, but the concrete mechanism is still unclear. This study aimed to investigate the effects of erythromycin on corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) and U937 cells (a human monocytic cell line). PBMCs were collected from non-smokers, healthy smoker volunteers, and COPD subjects. U937 cells were incubated with or without erythromycin and stimulated with TNF-α in the presence or absence of cigarette smoke extract (CSE). The dexamethasone (Dex) concentration required to achieve 50% inhibition of TNF-α-induced interleukin (IL)-8 production was determined and the mitogen-activated protein kinase (MAPK)/Activator protein-1 (AP-1) pathway was also evaluated. Erythromycin improved corticosteroid sensitivity in PBMCs obtained from COPD patients and CSE-treated U937 cells. This improvement in corticosteroid sensitivity was associated with reduced c-Jun expression, which resulted from the inhibition of P38 Mitogen-activated protein kinase (P38MAPK), extracellular signal-regulated protein kinase (ERK)1/2, and c-Jun N-terminal kinase (JNK) phosphorylation. Erythromycin had no effects on the phosphorylated and total protein expression levels of P38MAPK and ERK; however, it induced inhibition of the phosphorylated and total protein expression levels of JNK. This study provides evidence that erythromycin restores corticosteroid sensitivity in PBMCs and U937 cells. JNK inhibition by erythromycin restores corticosteroid sensitivity via the inhibition of c-Jun expression. Thus, JNK/c-Jun is a potential novel therapeutic target for COPD.

To investigate the chest CT imaging characteristics and clinical manifestations of patients with COVID-19 pneumonia.This study included 150 patients with COVID-19 pneumonia diagnosed from January 10 to February 12, 2020 to analyze their clinical and CT imaging characteristics.The period between symptom onset and initial CT examination ranged from 1 to 8 days. There were 83 cases (55.33%) involving both lungs, 67 cases (44.67%) involving a single lung (left 25 cases and right 42 cases). There were 49 cases (32.67%) of single intrapulmonary lesion, 33 cases (22.00%) of multiple intrapulmonary lesions, 68 cases (44.00%) of diffused intrapulmonary lesions, 67 cases (44.67%) of subpleural lesions, 24 cases (16.00%) of lesions localizing along the bronchovascular bundles, and 59 cases (39.33%) with lesions in both locations. There were 18 cases (12.00%) exhibiting ground-glass nodules of 10 mm, 124 cases (82.67%) of patchy ground-glass opacities with or without consolidation, 8 cases (5.33%) of cord-like lesions, 6 cases (4.00%) of pleural effusion, and 2 cases (1.33%) of enlarged lymph nodes.The main manifestations of initial chest CT in COVID-19 pneumonia patients was ground-glass opacities, commonly involving single site in patients 35 years old and multiple sites and extensive area in patients 60 years old. The common lesion sites were the subpleural region and the posterior basal segments of the lower lobes, mostly showing thickening of the interlobular septum and mixed with consolidation.

Long noncoding RNAs (lncRNAs) regulate a variety of physiological and pathological processes. However, the biological function of lncRNAs in mammalian germ cells remains largely unexplored. Here we identified one novel lncRNA (lncRNA2193) from single-cell RNA sequencing performed on porcine oocytes and investigated its function in oocyte meiosis. During in vitro maturation (IVM), from germinal vesicle (GV, 0 hr), GV breakdown (GVBD, 24 hr), to metaphase II stage (MII, 44 hr), the transcriptional abundance of lncRNA2193 remained stable and high. LncRNA2193 interference by small interfering RNA microinjection into porcine GV oocytes could significantly inhibit rates of GVBD and the first polar body extrusion, but enhance the rates of oocytes with a nuclear abnormality. Moreover, lncRNA2193 knockdown disturbed cytoskeletal organization (F-actin and spindle), and decreased DNA 5-methylcytosine (5mC) and histone trimethylation (H3K4me3, H3K9me3, H3K27me3, and H3K36me3) levels. The lncRNA2193 downregulation induced a decrease of 5mC level could be partially due to the reduction of DNA methyltransferase 3A and 3B, and the elevation of 5mC-hydroxylase ten-11 translocation 2 (TET2). After parthenogenetic activation of MII oocytes, parthenotes exhibited higher fragmentation but lower cleavage rates in the lncRNA2193 downregulated group. However, lncRNA2193 interference performed on mature MII oocytes and parthenotes at 1-cell stage did not affect the cleavage and blasctocyst rates of pathenotes. Taken together, lncRNA2193 plays an important role in porcine oocyte maturation, providing more insights for relevant investigations on mammalian germ cells.

The role of exosomes derived from endothelial cells (ECs) in the progression of atherosclerosis (AS) and inflammation remains largely unexplored. We aimed to investigate whether exosome derived from CD137‐modified ECs (CD137‐Exo) played a major role in AS and to elucidate the potential mechanism underlying the inflammatory effect. Exosomes derived from mouse brain microvascular ECs treated with agonist anti‐CD137 antibody were used to explore the effect of CD137 signalling in AS and inflammation in vitro and vivo. CD137‐Exo efficiently induced the progression of AS in ApoE−/− mice. CD137‐Exo increased the proportion of Th17 cells both in vitro and vivo. The IL‐6 contained in CD137‐Exo which is regulated by Akt and NF‐КB pathway was verified to activate Th17 cell differentiation. IL‐17 increased apoptosis, inhibited cell viability and improved lactate dehydrogenase (LDH) release in ECs subjected to inflammation induced by lipopolysaccharide (LPS). The expression of soluble intercellular adhesion molecule1 (sICAM‐1), monocyte chemoattractant protein‐1 (MCP‐1) and E‐selectin in the supernatants of ECs after IL‐17 treatment was dramatically increased. CD137‐Exo promoted the progression of AS and Th17 cell differentiation via NF‐КB pathway mediated IL‐6 expression. This finding provided a potential method to prevent local and peripheral inflammation in AS.

Effective therapeutic targets for triple-negative breast cancer (TNBC), a special type of breast cancer (BC) with rapid metastasis and poor prognosis, are lacking, especially for patients with chemotherapy resistance. Decitabine (DCA) is a Food and Drug Administration-approved DNA methyltransferase inhibitor that has been proven effective for the treatment of tumors. However, its antitumor effect in cancer cells is limited by multidrug resistance. Cancer stem cells (CSCs), which are thought to act as seeds during tumor formation, regulate tumorigenesis, metastasis, and drug resistance through complex signaling. Our previous study found that miR-155 is upregulated in BC, but whether and how miR-155 regulates DCA resistance is unclear. In this study, we demonstrated that miR-155 was upregulated in CD24- CD44+ BC stem cells (BCSCs). In addition, the overexpression of miR-155 increased the number of CD24- CD44+ CSCs, DCA resistance and tumor clone formation in MDA-231 and BT-549 BC cells, and knockdown of miR-155 inhibited DCA resistance and stemness in BCSCs in vitro. Moreover, miR-155 induced stemness and DCA resistance by inhibiting the direct target gene tetraspanin-5 (TSPAN5). We further confirmed that overexpression of TSPAN5 abrogated the effect of miR-155 in promoting stemness and DCA resistance in BC cells. Our data show that miR-155 increases stemness and DCA resistance in BC cells by targeting TSPAN5. These data provide a therapeutic strategy and mechanistic basis for future possible clinical applications targeting the miR-155/TSPAN5 signaling axis in the treatment of TNBC.

To unravel changes in the structures and digestibility of sweet potato starch in the roots during postharvest storage (0 to 20 days), starches are isolated and characterized in terms of amylose content, polyphenols amount, molecular molar mass (Mw), molecular reassociation and multi-scale reassociated structures after cooking. Results reveal that starch digestibility decreases with a concomitant increase on resistant starch (RS) fraction during the first 10 days. These changes are associated with an increase of ordered structures, amylose and polyphenols content as well as the starch fractions with molecular weight of (2.0–2.5) × 107 g/mol. However these trends get reversed at higher postharvesting periods. Correlation matrices reveal that the short-range ordered structures and starch molecular reassociation behavior of starch paste and polyphenol content are the key factors in determining the RS content. Besides, the short-range ordered structures, specific starch molecular weight distribution and amylose of starch paste can be tailored for modulating the digestibility by controlling the postharvest storage time. This study opens a promising pathway to tailor starch digestibility via simply controlling the postharvest storage time of starch-containing crops.

Cigarette smoke is a major effector of chronic obstructive pulmonary disease (COPD), and Th17 cells and dendritic cells (DCs) involve in the pathogenesis of COPD. Previous studies have demonstrated the anti-inflammatory effects of macrolides. However, the effects of macrolides on the cigarette smoke extract- (CSE-) induced immune response are unclear. Accordingly, in this study, we evaluated the effects of erythromycin (EM) on CSE-exposed DCs polarizing naïve CD4+ T cells into Th17 cells. DCs were generated from bone marrow-derived mononuclear cells isolated from male BALB/c mice and divided into five groups: control DC group, CSE-exposed DC group, CD40-antibody-blocked CSE-exposed DC group, and EM-treated CSE-exposed DC group. The function of polarizing CD4+ T cells into Th17 cells induced by all four groups of DCs was assayed based on the mixed lymphocyte reaction (MLR) of naïve CD4+ T cells. CD40 expression in DCs in the CSE-exposed group increased significantly compared with that in the control group (P<0.05). The Th17 cells in the CSE-exposed DC/MLR group increased significantly compared with those in the control DC/MLR group (P<0.05). Moreover, Th17 cells in the CD40-blocked CSE-exposed DC/MLR group and EM-treated CSE-exposed DC/MLR group were reduced compared with those in the CSE-exposed DC/MLR group (P<0.05). Thus, these findings suggested that EM suppressed the CSE-exposed DC-mediated polarization of CD4+ T cells into Th17 cells and that this effect may be mediated through inhibition of the CD40/CD40L pathway.

Fyn is a member of the protein tyrosine kinase family and its overexpression is associated with various types of inflammation. MicroRNAs can regulate the expression of target genes and play an important role in varied physiological and pathological processes. Based on the important role of Fyn and microRNA-125a-3p (miR-125a-3p) in inflammation, and combined with the bioinformatics studies, we performed in this study and chose miR-125a-3p as the focus of our research. During the progression of inflammation, we found that the expression of miR-125a-3p was decreased while the expression of Fyn was up-regulated. Fyn formed a complex with Neuropilin-1, which inhibited odontoblastic differentiation and expanded inflammatory responses through nuclear factor-κB signal pathways in dental pulp stem cells (DPSCs). These findings suggested that miR-125a-3p plays an important role in odontoblastic differentiation of DPSCs by targeting Fyn, implying its therapeutic potential in dental caries.

The objective of this study was to evaluate whether baseline 18F-fluorodeoxyglucose (FDG) uptake is associated with carotid plaque progression. A total of 156 subjects with carotid plaque were enrolled and underwent carotid magnetic resonance imaging (MRI) (at baseline and the 12-month follow-up) and positron emission tomography-computed tomography (PET-CT) (baseline). Carotid plaque progression was evaluated by two indices (the incidence of plaque progression and percentage of plaque increase) with three-dimensional (3D) imaging, while the 18F-FDG uptake was evaluated by the 18F-FDG uptake levels and 18F-FDG uptake velocity. The association between plaque progression and 18F-FDG uptake was investigated by the trend test and multivariate logistic regression analysis. Of the 156 subjects, 80 (51.3%) showed carotid plaque progression during the 12-month follow-up. Firstly, no association was found between 18F-FDG uptake levels and plaque progression. Secondly, significant differences in the incidence of plaque progression were observed among the groups with different uptake velocities, showing a significant decreasing trend ranging from high to intermediate to low (p = 0.002, trend test). After adjusting for covariates, an adequate prediction of the 18F-FDG uptake velocity for the incidence of plaque progression was revealed (OR = 0.682, p < 0.05). In addition, no association was found between the 18F-FDG uptake velocity and the percentage of plaque increase in the subjects with plaque progression (p = 0.757, trend test). Our findings suggest 18F-FDG uptake velocity is independently associated with the incidence of carotid plaque progression. Additionally, the 18F-FDG uptake velocity, as another important parameter of PET-CT, warrants further study in future clinical research. • The18F-FDG uptake levels were not associated with the carotid plaque progression. • The18F-FDG uptake velocity could predict the incidence of carotid plaque progression. • The18F-FDG uptake velocity with related factors warrants more attention in future clinical research.

Context: Core control and strength are important for reducing the risk of lower-extremity injury. Current evidence on the effect of core training in male adolescent athletes is limited, and other investigations into the effects of core training often emphasized core strength only. Objective: To examine whether core training emphasizing both control and strength of the trunk and hip would improve joint kinematics during landing, sports performance, and lower-extremity muscle strength in adolescent male volleyball athletes. Design: Single group pretest and posttest design. Setting: University laboratory. Participants: Sixteen male participants (age: 13.4 [1] y, height: 167.8 [8.6] cm, mass: 58.6 [13.9] kg, and volleyball experience: 3.8 [1.5] y) from a Division I volleyball team at a junior high school. Main Outcome Measurements: Kinematics of the trunk and lower-extremity during box landing and spike jump landing tasks, volleyball-related sports performance, and isokinetic strength of hip and knee muscles were assessed before and after a 6-week core training program. Results: After training, the participants demonstrated decreased trunk flexion angle (P = .01, Cohen’s d = 0.78) during the box landing task and reduced the maximum knee internal rotation angle (P = .04, Cohen’s d = 0.56) during the spike jump landing task. The average isokinetic strength of hip flexors and external rotators, and knee flexors and extensors also significantly increased (P = .001, Cohen’s d = 0.98; P = .04, Cohen’s d = 0.57; P = .02, Cohen’s d = 0.66; P = .003, Cohen’s d = 0.87, respectively); however, sports performance did not show significant changes. Conclusions: A more erect landing posture following training suggests that the core training program may be beneficial for improving core stability. The long-term effect of core training for knee injury prevention needs further investigation.

Background A distinct serum metabonomic pattern has been previously revealed to be associated with various forms of liver disease. Here, we aimed to apply mass spectrometry to obtain serum metabolomic profiles from individuals with cholangiocarcinoma and benign hepatobiliary diseases to gain an insight into pathogenesis and search for potential early-disease biomarkers. Methods Serum samples were profiled using a hydrophilic interaction liquid chromatography platform, coupled to a mass spectrometer. A total of 47 serum specimens from 8 cholangiocarcinoma cases, 20 healthy controls, 8 benign disease controls (bile duct strictures) and 11 patients with hepatocellular carcinoma (as malignant disease controls) were included. Data analysis was performed using univariate and multivariate statistics. Results The serum metabolome disparities between the metabolite profiles from healthy controls and patients with hepatobiliary disease were predominantly related to changes in lipid and lipid-derived compounds (phospholipids, bile acids and steroids) and amino acid metabolites (phenylalanine). A metabolic pattern indicative of inflammatory response due to cirrhosis and cholestasis was associated with the disease groups. The abundance of phospholipid metabolites was altered in individuals with liver disease, particularly cholangiocarcinoma, but no significant difference was seen between profiles from patients with benign biliary strictures and cholangiocarcinoma. Conclusion The serum metabolome in cholangiocarcinoma exhibited changes in metabolites related to inflammation, altered energy production and phospholipid metabolism. This study serves to highlight future avenues for biomarker research in large-scale studies.

Objective: Gout, induced by monosodium urate (MSU) crystal deposition in joint tissues, provokes severe pain and impacts life quality of patients. However, the mechanisms underlying gout pain are still incompletely understood. Methods: We established a mouse gout model by intra-articularly injection of MSU crystals into the ankle joint of wild type and genetic knockout mice. RNA-Sequencing, in vivo molecular imaging, Ca2+ imaging, reactive oxygen species (ROS) generation, neutrophil influx and nocifensive behavioral assays, etc. were used. Results: We found interleukin-33 (IL-33) was among the top up-regulated cytokines in the inflamed ankle. Neutralizing or genetic deletion of IL-33 or its receptor ST2 (suppression of tumorigenicity) significantly ameliorated pain hypersensitivities and inflammation. Mechanistically, IL-33 was largely released from infiltrated macrophages in inflamed ankle upon MSU stimulation. IL-33 promoted neutrophil influx and triggered neutrophil-dependent ROS production via ST2 during gout, which in turn, activated transient receptor potential ankyrin 1 (TRPA1) channel in dorsal root ganglion (DRG) neurons and produced nociception. Further, TRPA1 channel activity was significantly enhanced in DRG neurons that innervate the inflamed ankle via ST2 dependent mechanism, which results in exaggerated nociceptive response to endogenous ROS products during gout. Conclusions: We demonstrated a previous unidentified role of IL-33/ST2 in mediating pain hypersensitivity and inflammation in a mouse gout model through promoting neutrophil-dependent ROS production and TRPA1 channel activation. Targeting IL-33/ST2 may represent a novel therapeutic approach to ameliorate gout pain and inflammation.

Nelumbo nucifera leaf water extract (NLE) attenuates high-fat diet (HFD)-induced rabbit atherosclerosis, but its mechanism of action and the relevant compounds remain unclear. Modulating the proliferation and migration of vascular smooth muscle cells (VSMCs) may be an enforceable strategy for atherosclerosis prevention. Therefore, we investigated the potential mechanisms of N. nucifera leaf polyphenol extract (NLPE) and its active ingredient gallic acid (GA) in VSMC proliferation and migration. A7r5 rat aortic VSMCs were provoked using 50 ng mL-1 tumor necrosis factor (TNF)-α; the NLPE or GA reduced the TNF-α-induced migration by inhibiting the transforming protein RhoA/cell division cycle protein 42 pathway. The NLPE or GA suppressed the TNF-α-induced VSMC proliferation by inhibiting the Ras pathway and increasing the expression of phosphatase and tensin homolog (PTEN), kinase suppressor of Ras 2, and inducible nitric oxide synthase. The NLPE or GA increased PTEN expression by downregulating microRNA (miR)-21 expression and reduced Ras and RhoA expression by upregulating miR-143 and miR-145 expression. The NLPE and GA use potentially prevents atherosclerosis by inhibiting the VSMC migration and proliferation. The mechanisms involve the regulation of the miRNA in PTEN, the Ras/extracellular-signal-regulated kinase pathway, and Rho family proteins.

Background The Devereux Early Childhood Assessment for Toddlers (DECA-T), which is one of the few standardized, norm-referenced behavioral rating scales related to young children's mental health, resilience, and social-emotional development, was developed for toddlers aged between 18 and 36 months. Objective The aim of this study was to test the clinimetric properties of the Chinese (Traditional) version of the DECA-T (C-DECA-T) using a classical test theory analysis and an item response theory analysis. Methods Seventy-five community-based toddlers aged from 18 to 36 months and 50 clinic-based participants recruited in hospitals in northern Taiwan participated in this study. Social-emotional competence was assessed by the C-DECA-T and children's behavior problems were rated via the Child Behavior Checklist 1.5 to 5 (CBCL/1.5-5). Homogeneity of the C-DECA-T was assessed by Mokken analysis; sensitivity and specificity were assessed via receiver operating characteristic curve. Results The results showed the C-DECA-T demonstrated good test-retest reliability (r=0.8) and high internal consistency (Cronbach's alpha = 0.94). Inter-rater reliability between father and mother was fair (ICC = 0.46). Convergent validity of the CBCL/1.5-5 total behavior problems (r=-0.26) demonstrated acceptable psychometric performance. The overall measure of the sampling adequacy of the C-DECA-T assessed by principal component analysis was 0.93. Mokken scale analysis showed the 36-items of the C- DECA-T formed a weak unidimensional scale (Hs =0.35), supporting its construct validity. The area under curve of the C-DECA-T in prediction of social-emotional disturbance was 0.70. The optimal cutoff of the Total Protective Factor score of the C-DECA-T was a T score of 40.1 (T40.1), with a sensitivity of 95% and a specificity of 68%. Item 2 ("show affection for a familiar adult") and item 33 ("calm herself/himself") provide a good amount of information for the assessment of social-emotional strength and needs of a toddler in clinical practice. Conclusion The C-DECA-T showed good psychometric properties. Our findings of high internal consistency of the three subscales and total score of the C-DECA-T suggest symptom manifestation of social-emotional competence and needs in Taiwanese toddlers is not culturally different from American toddlers. The clinimetric properties of the C-DECA-T examined by a classical test theory analysis approach and an item response theory analysis approach suggest that the C-DECA-T is a reliable and valid instrument for measuring social-emotional strength and needs in the population in Taiwan.

The efficacy and tolerability of adding chemotherapy to radiotherapy in the era of intensity-modulated radiation therapy (IMRT) remain controversial among older patients with nasopharyngeal carcinoma (NPC). The present study compared IMRT alone with IMRT in combination with chemotherapy in elderly NPC patients. Between January 2011 and December 2014, 102 patients aged >65 years with NPC who received IMRT alone (IMRT group) or IMRT in combination with chemotherapy (IMRT/CT group) were enrolled. Patients from both treatment arms were pair-matched (1:1 ratio) based on six clinical factors. Differences in overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method and Cox proportional hazards models, whereas the toxicity profile was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4. No significant differences were noted in OS (72.1% vs. 72.5%, p = 0.799), DFS (65.9% vs. 70.1%, p = 0.733), LRRFS (76.4% vs. 71.6%, p = 0.184), and DMFS (90.8% vs. 98.0%, p = 0.610) between the IMRT and IMRT/CT groups. Multivariate analyses showed that chemotherapy was not an independent factor for OS, DFS, LRRFS, and DMFS. However, the incidences of grade 3 vomiting/nausea (p = 0.000), leukopenia/neutropenia (p = 0.000), thrombocytopenia (p = 0.041), and anemia (p = 0.040) were significantly higher in the IMRT/CT group compared with the IMRT group. No grade 4 toxicities were observed. IMRT alone was similar to IMRT/CT in treating elderly NPC patients (age >65 years), with comparable survival outcomes and less grade 3 toxicities.

Background. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder with recurrent abdominal pain and altered defecation habits. We here attempted to determine the effect of acupuncture on IBS. Methods. Randomized controlled trials (RCTs) published in CNKI, VIP, Wanfang, PubMed, Cochrane Library, EMBASE, Web of science, and ClinicalTrials.gov till July 17, 2019 were searched. Outcomes were total efficacy rates, overall IBS symptom scores, or global quality of life scores. Standardized mean difference (SMD) with 95% confidence intervals (CI) and risk ratio (RR) with 95% CI were calculated for meta-analysis. Results. We included 41 RCTs involving 3440 participants for analysis. 8 RCTs compared acupuncture with sham acupuncture, among which 3 trials confirmed the biological effects of acupuncture, especially in treating abdominal pain, discomfort, and stool frequency. No significant difference was found when acupuncture was compared with sham acupuncture, in terms of effects on IBS symptoms and quality of life (SMD = 0.18, 95% CI −0.26∼0.63, P=0.42; SMD = −0.10, 95% CI −0.31∼0.11, P=0.35), but the pooled efficacy rate data showed a better outcome for true acupuncture (RR = 1.22, 95% CI 1.01∼1.47, P=0.04), which was not supported by sensitivity analysis. Acupuncture was more effective relative to western medicine in alleviating IBS symptoms (RR = 1.17, 95% CI 1.12∼1.23, I2 = 0%, P<0.00001), whose effect might last 3 months. Besides, acupuncture as an adjunct to western medicine, Chinese medications, or tuina was superior over the single latter treatment (RR = 1.68, 95% CI 1.18 to 2.40, P=0.004; 1.19, 1.03 to 1.36, P=0.02; 1.36, 1.08 to 1.72, P=0.009, respectively), with high heterogeneities. Conclusions. Relative to sham controls, acupuncture showed no superiority for treating IBS, while the advantage over western medicine was significant. Acupuncture could be used as an adjunct in clinical settings to improve efficacy. Future high-quality and large-sample-size studies with adequate quantity-effect design need to be conducted.

Background Headache attacks severely impaired life quality and increase the economic burden of migraineurs. Electroacupuncture (EA) has been used worldwidely to treat several pain-related diseases including migraines. However, whether EA with low or high frequency exerts a distinct analgesic effect remains unknown and needs further study. Methods/Design This study is a randomised, single-blinded, placebo-controlled trial with three parallel arms. A total of 144 migraine outpatients will be randomly allocated to the 2 Hz EA group, 100 Hz EA group and placebo control group. The duration of the trial is 20 weeks, including a 4-week-long baseline assessment period (weeks − 4–0), a 4-week-long treatment period (weeks 1–4) and a 12-week-long follow-up period (weeks 5–16). Twelve treatment sessions will be performed over a 4-week period (weeks 1–4). The primary outcome will be measured by the frequency of migraine attacks in the past 4 weeks at the end of week 4 post-randomisation. The secondary outcome will be measured by the frequency of migraine attacks in the past 4 weeks at the end of weeks 8, 12 and16 post-randomisation; number of days with migraine; dosage of ibuprofen; the scores of visual analogue scale (VAS); Self-Rating Anxiety Scale (SAS); Self-Rating Depression Scale (SDS); and Migraine Specific Quality of Life questionnaire (MSQ) in the past 4 weeks at the end of weeks 4, 8, 12 and 16 post-randomisation. Safety assessment, compliance and blinding evaluation will be carried out at the end of week 16 post-randomisation. Discussion The recruitment will be started on 1 June 2021 and expected to finish on 31 May 2023. We aimed to clarify the dominant frequency of EA on headache attacks in a migraineur. Trial registration Chinese Clinical Trial Registry ChiCTR-1800017259. Registered on 20 July 2018.

Background Patients with Parkinson’s disease (PD) can develop impulse control disorders (ICDs) while undergoing a pharmacological treatment for motor control dysfunctions with a dopamine agonist (DA). Conventional clinical interviews or questionnaires can be biased and may not accurately diagnose at the early stage. A wearable electroencephalogram (EEG)-sensing headset paired with an examination procedure can be a potential user-friendly method to explore ICD-related signatures that can detect its early signs and progression by reflecting brain activity. Methods A stereotypical Go/NoGo test that targets impulse inhibition was performed on 59 individuals, including healthy controls, patients with PD, and patients with PD diagnosed by ICDs. We conducted two Go/NoGo sessions before and after the DA-pharmacological treatment for the PD and ICD groups. A low-cost LEGO-like EEG headset was used to record concurrent EEG signals. Then, we used the event-related potential (ERP) analytical framework to explore ICD-related EEG abnormalities after DA treatment. Results After the DA treatment, only the ICD-diagnosed PD patients made more behavioral errors and tended to exhibit the deterioration for the NoGo N2 and P3 peak amplitudes at fronto-central electrodes in contrast to the HC and PD groups. Particularly, the extent of the diminished NoGo-N2 amplitude was prone to be modulated by the ICD scores at Fz with marginal statistical significance (r = − 0.34, p = 0.07). Conclusions The low-cost LEGO-like EEG headset successfully captured ERP waveforms and objectively assessed ICD in patients with PD undergoing DA treatment. This objective neuro-evidence could provide complementary information to conventional clinical scales used to diagnose ICD adverse effects.

A novel polysaccharide (CMP-2B) was purified from Centipeda minima by anion-exchange and gel-permeation chromatography. Structural characterization revealed that CMP-2B was a homogeneous heteropolysaccharide with an average molecular weight of 113.193 KDa. CMP-2B was made up of mannose, galacturonic acid, galactose and arabinose with a molar ratio of 0.27:0.12:0.42:0.17. The backbone chain of CMP-2B consisted of 3,6)-α-D-Manp-(1 and 4,6)-β-D-Galp-(1, and the branches were comprised of 4)-α-D-GalpA-(1, 6)-β-D-Galp-(1, T-α-L-Araf-(1 and 3)-α-L-Araf -(1. Besides, the results of antioxidant assays revealed that CMP-2B possessed signifcant free radical scavenging ability. Moreover, the results of hypoglycemic assays showed that CMP-2B displayed α-glucosidase inhibitory activities, and could significantly improve glucose consumption, glycogen synthesis and the activity of pyruvate kinase of insulin-resistance HepG2 cells. Overall, these results suggested that CMP-2B could be a new source for functional foods.

Increasing studies strongly prove that renal denervation, a minimally invasive surgery, is a promising new non-drug treatment method that can effectively control blood pressure in patients with resistant hypertension, but the evaluation of the long-term blood pressure control effect of renal denervation for resistant hypertension is still lacking. Here, we critically review current long-term follow-up data about the use of renal denervation for RH to comprehensively evaluate the effectiveness of renal denervation for RH, and to provide practical guidance for practitioners who are establishing a renal denervation service. Limited by the current research, many problems need to be solved before renal denervation is applied to RH. In addition, ambulatory blood pressure should be the first choice for the evaluation of blood pressure. Finally, the continuous antihypertensive effect of renal denervation in different renal denervation systems also needs to be strictly compared.

This study compared the effect of whole lung lavage (WLL) at different time-points early after exposure of the respiratory system to insoluble radioactive particles.Forty adult beagles were randomized into a control group and the 3-h, 8-h, 24-h, and 48-h lavage groups (The lavage groups showed similarly increasing trends for serum U levels from DU exposure to 3 and 7 days after exposure; however, these values were significantly lower than those in the control group (The best effect of WLL after exposure of the respiratory system to insoluble radioactive particles was achieved at 3 h, followed by 8 h; there was no difference in the effectiveness of lung lavage at 24 h and 48 h.

Chronic pain is a costly health problem that impairs health-related quality of life when not effectively treated. Regulating the transition from acute to chronic pain is a new therapeutic strategy for chronic pain that presents a major clinical challenge. The underlying mechanisms of pain transition are not entirely understood, and strategies for preventing this transition are lacking. Here, a hyperalgesic priming model was used to study the potential mechanism by which γ-aminobutyric acid receptor type A (GABAAR) in the dorsal root ganglion (DRG) contributes to pain transition. Furthermore, electroacupuncture (EA), a modern method of acupuncture, was administered to regulate pain transition, and the mechanism underlying EA’s regulatory effect was investigated. Hyperalgesic priming was induced by intraplanar injection of carrageenan (Car)/prostaglandin E2 (PGE2). The decrease in mechanical withdrawal threshold (MWT) induced by PGE2 returned to baseline 4 h after injection in NS + PGE2 group, and still persisted 24 h after injection in Car + PGE2 group. Lower expression of GABAAR in the lumbar DRG was observed in the model rats. Furthermore, activating or blocking GABAAR could reversed the long-lasting hyperalgesia induced by Car/PGE2 injection or produced a persistent hyperalgesia. In addition, GABAAR may be involved in Protein Kinase C epsilon (PKCε) activation in the DRG, a mark molecular of pain transition. EA considerably increased the mechanical pain thresholds of hyperalgesic priming model mammals in both the acute and chronic phases. Furthermore, EA upregulated the expression of GABAAR and inhibited the activation of PKCε in the DRG. In addition, peripheral administration of picrotoxin blocked the analgesic effect of EA on the model rats and abolished the regulatory effect of EA on PKCε activation. These findings suggested that GABAAR plays a key role in both the transition from acute to chronic pain and the analgesic effect of EA on hyperalgesic priming.