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The gut microbiota is known to be associated with the regulation of many neurological diseases and behaviors, including chronic pain. However, it is unclear whether the gut microbiota is critical to the itch sensation. In this study, we investigated the effects of gut microbiota depletion on acute itch.First, an antibiotic cocktail was orally administered to deplete the gut microbiota in male C57BL/6 mice. Then, pruritogens were intradermally injected to induce acute itch behavior. In addition, antibiotic-treated mice received transplantation of fecal microbiota from untreated mice, followed by tests for acute itch. The changes in c-Fos expression in trigeminal ganglia (TG) neurons were also investigated by immunofluorescence staining.Our results indicated that chronic antibiotic treatment significantly reduced the diversity and richness of the gut microbiota of mice. Compared to vehicle-treated mice, antibiotic-treated mice showed reductions in acute itch behavior induced by compound 48/80, chloroquine (CQ), and serotonin (5-HT), respectively. Moreover, repositioning of microbiota reversed the reductions in acute itch behavior in antibiotic-treated mice. In addition, immunofluorescence staining revealed that antibiotic-treated mice displayed decreased c-Fos expression in ipsilateral TG compared to controls.Our study, for the first time, discovered that antibiotic-induced gut microbiota depletion could reduce acute itch behavior, which may be connected with decreased TG neuronal activity.

Background Low voltage zones (LVZ) are associated with poor outcomes in patients with atrial fibrillation (AF). The APPLE and DR-FLASH scores predict LVZ in patients undergoing catheter ablation. This study aimed to assess the relationship of mitral valve regurgitation (MR) and LVZ after adjusting for APPLE or DR-FLASH scores. Methods This was a retrospective study on patients with AF who underwent their first catheter ablation. All patients underwent a transthoracic echocardiographic examination before ablation. The APPLE and DR-FLASH scores were calculated at baseline. LVZ determined by high-density mapping was defined as bipolar voltage amplitude 5% of the left atrial surface area. Results Altogether, 152 patients (mean age 62.0 ± 10.8 years, 65.8% men, and 36.2% with persistent AF) were included. Of the 152 patients, 47 (30.9%) had LVZ. The patients with LVZ had more moderate-to-severe MR (17.0% vs. 3.8%, P = 0.014) and higher APPLE scores (1.7 ± 1.1 vs. 1.2 ± 1.1, P = 0.009) and DR-FLASH scores (3.0 ± 1.5 vs. 2.4 ± 1.4, P = 0.010). Using multivariate logistic regression analysis, we found moderate-to-severe MR was related to LVZ presence after adjusting for the APPLE (OR 4.040, P = 0.034) or DR-FLASH (OR 4.487, P = 0.020) scores. Furthermore, moderate-to-severe MR had an incremental predictive value for LVZ presence in addition to the APPLE (P = 0.03) or DR-FLASH (P = 0.02) scores. Conclusion In patients with AF, MR severity was related to LVZ after adjusting the APPLE score or DR-FLASH score.

We previously reported that a multifunctional opioid/neuropeptide FF receptor agonist, DN-9, achieved peripherally restricted analgesia with reduced side effects. To develop stable and orally bioavailable analogues of DN-9, eight lactam-bridged cyclic analogues of DN-9 between positions 2 and 5 were designed, synthesized, and biologically evaluated. In vitro cAMP assays revealed that these analogues, except 7, were multifunctional ligands that activated opioid and neuropeptide FF receptors. Analogue 1 exhibited improved potency for κ-opioid and NPFF2 receptors. All analogues exhibited potent, long-lasting, and peripherally restricted antinociception in the tail-flick test without tolerance development after subcutaneous administration and produced oral analgesia. Oral administration of the optimized compound analogue 1 exhibited powerful, peripherally restricted antinociceptive effects in mouse models of acute, inflammatory, and neuropathic pain. Remarkably, orally administered analogue 1 had no significant side effects, such as tolerance, dependence, constipation, or respiratory depression, at effective analgesic doses.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are an effective treatment for common EGFR mutations in non-small-cell lung cancer (NSCLC). Rarer EGFR mutations such as kinase domain duplications (KDDs) have been identified, but the optimal therapy following treatment resistance remains unknown. We report two patients who were diagnosed with NSCLC including KDD. For case 1, afatinib (40 mg once daily) was at first effective but then became ineffective. Consequently, osimertinib therapy (80 mg once daily) was administered. As of 26 May 2021, the osimertinib therapy achieved a stable disease state according to the chest computed tomography scan. As for case 2, the patient received second-line chemotherapy and anlotinib (12 mg once daily) for 6 months and died in May 2020. Here, we describe osimertinib as an effective therapy for EGFR-KDD positive lung adenocarcinoma and thereby provide a new alternative for further treatment following resistance to first- and second-generation EGFR-TKIs.

ALK-positive disease is characterized by the presence of ALK gene rearrangements that encode driver fusion oncoproteins. EML4-ALK fusion is regarded as the most common type in advanced nonsmall cell lung cancers. STRN-ALK is a novel ALK fusion partner in NSCLC and is considered sensitive to targeted therapy. However, there was no study regarding effective therapy for EML4-ALK and STRN-ALK double fusion variants in EGFR-resistant mutant lung cancer. TP53, RB1, and EGFR exon 21 L858R were found in tumor tissues and plasma from patients with capture-based NGS. After 3 months of gefitinib treatment, an NGS of plasma circulating tumor DNA showed that all variants disappeared significantly, and the tumor mass regressed on CT. However, after 10 months, the patient developed drug resistance and the disease progressed with the appearance of new metastatic lesions in the liver and bones. A repeated NGS test revealed EGFR exon20 T790M and the appearance of a novel double-fusion EML4-ALK and STRN-ALK. A combined therapeutic regimen of crizotinib plus osimertinib showed a promising prognosis confirmed with lung CT scans showing stable lesions without any new metastasis. Moreover, a subsequent genotype by NGS also showed the disappearance of STRN-ALK and EGFR exon20 T790M. The therapeutic efficacy of crizotinib plus osimertinib on EML4-ALK and STRN-ALK double-fusion variant in patients with EGFR-resistant mutant lung cancer may provide a supportive reference for the patients with such genetic alteration.

Background This study aimed to evaluate the presence of symptoms of Internet Gaming Disorder (IGD) and examined associations between IGD and depressive symptoms, family and peer support among male college students in Nanchong, China. Methods A cross-sectional study was conducted among 2533 male students in three colleges. Background characteristics, depressive symptoms, family and peer support and IGD information were collected. Binary logistic regression was performed to access the relationship between variables and IGD. PROCESS macro was used to examine the mediation analysis of family and peer support on the relationship between depressive symptoms and IGD. Results The estimated presence of symptoms of IGD was 11.6%. The most commonly endorsed items were escapism, continuation and preoccupation both among total participates and the IGD group. In the binary logistic regression, general expenditure per month, depressive symptoms, and family and peer support revealed their significance in associations with IGD. Adjusted for the significant background variable, depressive symptoms and family and peer support remained significance. Additionally, family and peer support would attenuate the relationship between depressive symptoms and IGD. Conclusions This study found that one in ten male college students reported clinically significant IGD symptoms, which indicate that IGD is an important public health problem in Nanchong, China.

Objective The association between the shedding of the endothelial glycocalyx (EG) and the pathogenesis of microcirculatory perfusion disturbances has been discussed in experimental studies. This discussion, however, has limited relevance in a clinical setting. We investigated EG shedding in patients undergoing cardiopulmonary bypass (CPB) and its association with alterations in microvascular perfusion. Methods The plasma levels of syndecan-1, heparan sulfate, and hyaluronan were used as markers of glycocalyx degradation. Microcirculatory parameters included perfused vessel density (PVD) and De Backer Scores. Sidestream dark field imaging (SDF) was applied to visualize sublingual microcirculation during the preoperative resting state (T0), after sternum splitting, after aortic clamping, 5 min before aortal declamping, 1 h after CPB (T4), 4 h after CPB, 24 h after CPB (T6), and 48 h after CPB. Results Thirty patients undergoing cardiac surgery were recruited. The plasma levels of glycocalyx degradation markers increased after CPB. This increase indicated severe glycocalyx shedding at T4 relative to that at T0. By T6, the plasma levels of glycocalyx degradation markers had decreased to baseline levels in a stepwise manner. PVD and the De Backer Scores decreased at T4 and recovered at T6. Glycocalyx marker concentrations were correlated with microvascular alterations during cardiac surgery. Conclusions Glycocalyx components are closely related to microcirculation perfusion disorders. Damage to the glycocalyx during surgery with CPB may play a key role in microcirculation perfusion dysfunction.

BACKGROUND Cardiac involvement occurs in more than half of the patients with light-chain amyloidosis (AL), but the characteristics, treatment and prognosis of cardiac AL (CAL) are not fully described. Methods and Results: A total of 227 patients with CAL diagnosis between January 2009 and March 2017 at Peking Union Medical College Hospital were included. Patients with Mayo stages I, II and III AL accounted for 0.9%, 49.8% and 49.3%, respectively. Autologous stem cell transplantation, bortezomib combinations, non-bortezomib regimens and palliative treatment were given as first line therapy in 3.1%, 44.1%, 30.8% and 22.0% of patients, respectively. Overall hematological response and cardiac response were achieved in 60.6% and 37.2% of evaluable patients, respectively. The median overall survival (OS) was 17 months in all patients, and 10 months in those with Mayo stage III. In patients with Mayo stage III disease who survived for >1 month, the bortezomib group survived significantly longer than the non-bortezomib group (median OS, not reached vs. 12 months, P=0.019). Three independent prognostic factors for survival were identified: N-terminal fragment of B-type natriuretic peptide (NT-proBNP) ≥5,000 pg/mL, bone marrow plasma cells ≥10%, and systolic blood pressure

It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF1 receptor antagonist/NPFF2 receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism. Furthermore, EKR and RKE completely blocked the NPFF2 receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems.

Background Coronavirus disease 2019 (COVID‐19) has reached a pandemic level. Cardiac injury is not uncommon among COVID‐19 patients. We sought to describe the electrocardiographic characteristics and to identify the prognostic significance of electrocardiography (ECG) findings of patients with COVID‐19. Hypothesis ECG abnormality was associated with higher risk of death. Methods Consecutive patients with laboratory‐confirmed COVID‐19 and definite in‐hospital outcome were retrospectively included. Demographic characteristics and clinical data were extracted from medical record. Initial ECGs at admission or during hospitalization were reviewed. A point‐based scoring system of abnormal ECG findings was formed, in which 1 point each was assigned for the presence of axis deviation, arrhythmias, atrioventricular block, conduction tissue disease, QTc interval prolongation, pathological Q wave, ST‐segment change, and T‐wave change. The association between abnormal ECG scores and in‐hospital mortality was assessed in multivariable Cox regression models. Results A total of 306 patients (mean 62.84 ± 14.69 years old, 48.0% male) were included. T‐wave change (31.7%), QTc interval prolongation (30.1%), and arrhythmias (16.3%) were three most common found ECG abnormalities. 30 (9.80%) patients died during hospitalization. Abnormal ECG scores were significantly higher among non‐survivors (median 2 points vs 1 point, p

Objective Pulmonary arterial hypertension (PAH) is a serious complication of SSc with high mortality. Interventricular systolic asynchrony (IVSA) is observed in PAH patients, but the effect of IVSA and its association with long-term mortality and clinical events in SSc-associated PAH are unclear. This study aimed to investigate the impact of IVSA on the prognosis of SSc-associated PAH. Methods Between March 2010 and July 2018, a total of 60 consecutive patients with SSc-associated PAH were enrolled. The end point was a composite of all-cause mortality and clinical worsening. Asynchrony was assessed by colour-coded tissue Doppler imaging (TDI) echocardiography. The myocardial sustained systole curves (Sm) of the basal portion of the right ventricular (RV) free wall and left ventricular (LV) lateral wall were obtained. IVSA was defined as the time difference from the onset of the QRS complex to the end of Sm between LV and RV. Results Patients with greater IVSA time differences presented with advanced pulmonary vascular resistance (PVR). The IVSA time difference was an independent predictive factor (Hazard Ratio (HR) = 1.018, 95% CI: 1.005, 1.031, P =0.005) for the composite end point and was significantly associated with PVR (r = 0.399, R2=0.092, P =0.002). Kaplan–Meier survival curves showed that patients with greater IVSA had worse prognoses (log-rank P =0.001). Conclusion In conclusion, IVSA analysed by colour-coded TDI echocardiography provided added value as a noninvasive, easy-to-use approach for assessing the prognosis of patients with SSc-associated PAH. A significant IVSA time difference identifies the subgroup of patients at high risk of a poor prognosis.

In a previously described chimeric peptide, we reported that the multifunctional opioid/neuropeptide FF (NPFF) receptor agonist 0 (BN-9) produced antinociception for 1.5 h after supraspinal administration. Herein, four cyclic disulfide analogs containing l- and/or d-type cysteine at positions 2 and 5 were synthesized. The cyclized analogs and their linear counterparts behaved as multifunctional agonists at both opioid and NPFF receptors in vitro and produced potent analgesia without tolerance development. In comparison to 0, cyclized peptide 6 exhibited sevenfold more potent μ-opioid receptor agonistic activity in vitro. Interestingly, the cyclized analog 6 possessed an improved stability in the brain and an increased blood-brain barrier permeability compared to the parent peptide 0 and produced more potent analgesia after supraspinal or subcutaneous administration with improved duration of action of 4 h. In addition, antinociceptive tolerance of analog 6 was greatly reduced after subcutaneous injection compared to fentanyl, as was the rewarding effect, withdrawal reaction, and gastrointestinal inhibition.

Right ventricular (RV) failure is a major cause of death in patients with pulmonary arterial hypertension, and the mechanism of RV failure remains unclear. While the malfunction of RyR2 (ryanodine receptor type 2) on sarcoplasmic reticulum (SR) and aberrant Ca

Aims Deep burn-wounds undergo a dynamic progression in the initial or periburn area after insults, and the zone of stasis is the crucial region suffering the deterioration, considered as salvageable. Few studies explored the role of mitochondria in this process. This study is to clarify a possible “built-in” protection of mitophagy. Main methods A classic “comb” scald rat model was established. Histological and blood-flow observation were processed based on hematoxylin-eosin staining and laser analysis. Oxidative and apoptotic status were analyzed by commercial kits. Transmission-electron microscope, immunofluorescence staining, and western blot were applied to detect the mitophagy in the zone of stasis and potential regulators. Adenovirus-based gene-silence contributed to determine the role of HIF-1α as a regulatory mediator. Key findings We found that burn-caused typical ischemia and histological deterioration in the zone of stasis, in parallel with increases in oxidative stress and apoptosis. Mitochondrial damage was involved in the aforementioned changes. Furthermore, we detected mitophagy in burn-wounds, which was contradictory to the burn-wound conversion. HIF-1α expression was closely related to the level of mitophagy, while BNIP3 and PARKIN are involved downstream. Significance We demonstrate that burn-induced mitochondrial impairment contributes to the mobilization of injurious mechanisms in the zone of stasis and that mitophagy provides a beneficial way to protect against burn-wound progression via the elimination of damaged mitochondria. Our findings offer insights into mitochondrial quality control in burn-wound progression and suggest the novel concept that HIF-1α may be a therapeutic target due to its possible regulation on BNIP3- or PARKIN-mediated mitophagy.

Pulmonary arterial hypertension is a serious complication of systemic lupus erythematosus. It is characterized by increased right ventricular afterload which mainly comprises pulmonary arterial compliance (PAC) and pulmonary vascular resistance. The role of PAC in predicting the outcome of systemic lupus erythematosus-associated pulmonary arterial hypertension has not been investigated yet. Between February 2012 to December 2016, 120 consecutive patients diagnosed with systemic lupus erythematosus-associated pulmonary arterial hypertension based on right heart catheterization were enrolled, prospectively. Baseline clinical characteristics and hemodynamic assessment were analyzed. Baseline right ventricular afterload was stratified according to the PAC and pulmonary vascular resistance. The end point was a composite of all-cause mortality and clinical worsening. Among them, end points occurred in 49 (41%) patients after 15 months (interquartile range, 8.5–24.0). Patients with a PAC P=0.001) of the end point events than the patients with a PAC ≥1.39 mL/mm Hg. Multivariable Cox regression analysis showed that stratified right ventricular afterload was the only independent predictor for the end point (hazard ratio, 2.009 [95% CI, 1.390–2.904],P2, 6.10;P

Background Atrial fibrillation (AF) is the most common sustained arrhythmia, and catheter ablation has been shown to be a highly effective treatment for patients with symptomatic AF. Very early recurrence (VER) of AF within 7 days after catheter ablation is common, but the clinical significance of VER remains unclear. We have examined the usefulness of the noninvasive electrocardiography monitor for the detection of VER and the relationship between VER and late recurrence (LR). Methods Eighty‐eight patients with paroxysmal or persistent atrial fibrillation were retrospectively included. All patients underwent primary catheter ablation at a large general hospital between March 2016 and August 2018. All patients were followed up in atrial fibrillation clinic at an interval of every 3 months for late recurrence of AF. VER was evaluated by one‐lead continuous noninvasive electrocardiography monitoring device for 7 days after ablation. The association between VER and LR was analyzed by univariate and multivariate Cox regression model. Results Mean age was 62.9 ± 9.7 years, and 39.8% were female. Thirty‐two patients (36.4%) experienced VER. After a mean follow‐up of 539.36 ± 211.66 days, 17 patients (19.3%) experienced LR. Multivariate Cox regression analysis revealed VER was an independent predictor of LR: HR 3.6 (95% CI, 1.2–10.8), p = .020. In addition, diabetes was also associated with LR of atrial fibrillation. Conclusions Noninvasive electrocardiography monitoring was a useful tool for detecting VER and VER after catheter ablation was associated with LR.

Background In the past two decades, chronic non-communicable diseases have become the leading disease burden, and cardio-cerebrovascular diseases (CCVD) are the main causes of death in chronic diseases. It has become the focus of global public health attention, in this study, System of Health Accounts 2011 (SHA 2011) is used to calculate health expenditure, discuss its economic burden, and put forward countermeasures. Methods Data were collected by multi-stage stratified random sampling and the medical expenses of patients with CCVD were calculated based on SHA 2011, from the dimensions of the financing plan, institutional flow, and service function. Correlation and regression analysis were conducted by controlling factors influencing hospitalization expenses. All analysis were conducted by software SPSS. Results The current health expenditure (CHE) of CCVD in Dalian was 3.986 billion Yuan, accounting for 12.88% of the CHE (30.947 billion Yuan). The current curative expenditure (CCE) of CCVD was 2.947 billion Yuan. 40.39% of CCVD financing came from social medical insurance, and the proportion of family health financing was higher (39.06%). The expenditures were consumed by general hospitals and elderly patients. Conclusions The expenditure burden of CCVD in Dalian was massive, and wasted the health resource severely. It is necessary for the government to adjust the financing structure, reallocate the expenses of CCVD, and make institutional flow and functional distribution more reasonable.

Ganoderma lucidum has salutary effects on tumor treatment, including pancreatic cancer and hepatocellular carcinoma. However, the molecular mechanisms underlying Ganoderma lucidum therapy is obscure. In this study, the Hepa1-6-bearing C57 BL/6 mouse model was utilized to explore the therapeutic efficacy of Ganoderma lucidum extract (GLE), documenting that it could effectively inhibit tumor growth. The microRNA (miRNA) profiles of GLE-treated and untreated mice were detected, and 25 differentially expressed (DE) miRNAs were determined, including 24 up-expressed and one down-expressed miRNAs. Using the ClusterOne algorithm, 8 hub miRNAs were isolated from the established miRNA-target network. The qRT-PCR assay demonstrated that these 8 miRNAs were up-expressed in the GLE treated tumor mice. Furthermore, the mRNA profiles showed that there are 76 DE mRNAs between GLE treated and model groups. The protein-protein interaction (PPI) network shows that Cntn1, Irs1, Nfkbia, Rybp and Ywhaz playing important roles, and qRT-PCR further revealed they were down-expressed in GLE treated Hepa1-6-bearing C57 BL/6 mice. The rebuilt miRNA-target network was shown that these 5 mRNAs were regulated by mmu-mir-23a-5p, -3102-3p, -337-3p, and -467a-3p, respectively. This study suggested that these 4 interesting miRNAs were potential biomarkers for evaluation of GLE efficacy, which may down-regulate the expression of Cntn1, Irs1, Nfkbia, Rybp and Ywhaz, and mediate many signaling pathways occurring in tumor treatment.

Background Styrax, one of the most famous folk medicines, has been frequently used for the treatment of cardiovascular diseases and skin problems in Asia and Africa. It is unclear whether Styrax or Styrax-related herbal medicines may trigger clinically relevant herb-drug interactions. Purpose This study was carried out to investigate the inhibitory effects of Styrax on human cytochrome P450 enzymes (CYPs) and to clarify whether this herb may modulate the pharmacokinetic behavior of the CYP-substrate drug warfarin when co-administered. Study Design The inhibitory effects of Styrax on CYPs were assayed in human liver microsomes (HLM), while the pharmacokinetic interactions between Styrax and warfarin were investigated in rats. The bioactive constituents in Styrax with strong CYP3A inhibitory activity were identified and their inhibitory mechanisms were carefully investigated. Methods The inhibitory effects of Styrax on human CYPs were assayed in vitro, while the pharmacokinetic interactions between Styrax and warfarin were studied in rats. Fingerprinting analysis of Styrax coupled with LC-TOF-MS/MS profiling and CYP inhibition assays were used to identify the constituents with strong CYP3A inhibitory activity. The inhibitory mechanism of oleanonic acid (the most potent CYP3A inhibitor occurring in Styrax) against CYP3A4 was investigated by a panel of inhibition kinetics analyses and in silico analysis. Results In vitro assays demonstrated that Styrax extract strongly inhibited human CYP3A and moderately inhibited six other tested human CYPs, as well as potently inhibited warfarin 10-hydroxylation in liver microsomes from both humans and rats. In vivo assays demonstrated that compared with warfarin given individually in rats, Styrax (100 mg/kg) significantly prolonged the plasma half-life of warfarin by 2.3-fold and increased the AUC(0-inf) of warfarin by 2.7-fold when this herb was co-administrated with warfarin (2 mg/kg) in rats. Two LC fractions were found with strong CYP3A inhibitory activity and the major constituents in these fractions were characterized by LC-TOF-MS/MS. Five pentacyclic triterpenoid acids (including epibetulinic acid, betulinic acid, betulonic acid, oleanonic acid and maslinic acid) present in Styrax were potent CYP3A inhibitors, and oleanonic acid was a competitive inhibitor against CYP3A-mediated testosterone 6β-hydroxylation. Conclusion Styrax and the pentacyclic triterpenoid acids occurring in this herb strongly modulate the pharmacokinetic behavior of warfarin via inhibition of CYP3A.

Pharmacological evidence indicated a functional interaction between neuropeptide FF (NPFF) and cannabinoid systems, and the cannabinoids combined with the NPFF receptor agonist neuropeptide VF (NPVF) produced antinociception without tolerance. In the present study, VF-13, a chimeric peptide containing the pharmacophores of the endogenous cannabinoid peptide VD-hemopressin(α) (VD-Hpα) and NPVF, was synthesized and pharmacologically evaluated. In vitro, VF-13 significantly upregulated the phosphorylated level of extracellular signal-regulated kinase 1/2 (ERK1/2) in CHO cells stably expressing CB1 receptors and inhibited forskolin-induced cAMP accumulation in HEK293 cells stably expressing NPFF1 or NPFF2 receptors. Moreover, VF-13 induced neurite outgrowth in Neuro 2A cells via CB1 and NPFF receptors. These results suggest that VF-13 exhibits multifunctional agonism at CB1, NPFF1 and NPFF2 receptors in vitro. Interestingly, intracerebroventricular VF-13 produced dose-dependent antinociception in mouse models of tail-flick and carrageenan-induced inflammatory pain via the TRPV1 receptor. In contrast, the reference compound (m)VD-Hpα-NH2 induced CB1 receptor-mediated supraspinal antinociception. Additionally, subcutaneous injection of (m)VD-Hpα-NH2 and VF-13 produced significant antinociception in carrageenan-induced inflammatory pain model. In the tetrad assay, our data demonstrated that VF-13 elicited hypothermia, but not catalepsy and hypoactivity after intracerebroventricular injection. Notably, VF-13 produced non-tolerance forming antinociception over 6 days treatment in both acute and inflammatory pain models. Furthermore, VF-13 had no apparent effects on gastrointestinal transit, pentobarbitone-induced sedation, food intake, and motor coordination at the supraspinal level. In summary, VF-13, a novel chimeric peptide of VD-Hpα and NPVF, produced non-tolerance forming antinociception in preclinical pain models with reduced cannabinoid-related side effects.

Orofacial pain is one of the most common pain conditions and compromises the quality of life of the sufferer. Several studies have shown that opioid agonists produced significant analgesia in the orofacial pain, and combination of opioids with drugs belonging to other classes induced synergism in the orofacial pain. However, combination therapy of different analgesic drugs improves the risk of drug-drug interactions. Against this background, we sought to investigate the analgesic effects of the multi-functional opioid peptide DN-9, a mixed opioid and NPFF receptors agonist that produced robust analgesia in acute and inflammatory pain models, on formalin-induced orofacial pain. Our results showed that formalin injection caused significant spontaneous pain behaviors and increased the expressions of the mu-opioid receptor, c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) in the ipsilateral trigeminal ganglion (TG). In mice pretreated with DN-9, there was a significant reduction in nociceptive behaviors, which was selectively mediated by the mu- and kappa-opioid receptors, independently of the NPFF system. Four hours after formalin injection, the level of c-Fos immunoreactivity in the ipsilateral TG neurons was much lower in mice pretreated with DN-9 or morphine. In addition, DN-9 exhibited a significant inhibition in the expression of p-ERK1/2, which was reversed by the selective antagonists of the mu- and kappa-opioid receptors. In conclusion, our present results demonstrate that central administration of DN-9 produces potential antinociceptive effects via the mu- and kappa-opioid receptors, independently of the NPFF system, and this antinociceptive action is tightly linked with the intracellular ERK activation in TG neurons.

Background Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action. Whereas several lines of evidence suggest that endomorphins, the endogenous mu-opioid agonists, attenuate acute and chronic pain at the spinal level, their preemptive analgesic effects remain to be determined. In this study, we evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mouse model of inflammatory pain. Methods The anti-allodynic activities of preemptive intrathecal administration of endomorphin-1 and endomorphin-2 were investigated in complete Freund’s adjuvant (CFA)-induced inflammatory pain model and paw incision-induced postoperative pain model. The modulating effects of endomorphins on the expression of p38 mitogen-activated protein kinase (p38 MAPK) and inflammatory mediators in dorsal root ganglion (DRG) of CFA-treated mice were assayed by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, or immunofluorescence staining. Results Preemptive intrathecal injection of endomorphins dose-dependently attenuated CFA-induced mechanical allodynia via the mu-opioid receptor and significantly reversed paw incision-induced allodynia. In addition, CFA-caused increase of phosphorylated p38 MAPK in DRG was dramatically reduced by preemptive administration of endomorphins. Repeated intrathecal application of the specific p38 MAPK inhibitor SB203580 reduced CFA-induced mechanical allodynia as well. Further RT-PCR assay showed that endomorphins regulated the mRNA expression of inflammatory cytokines in DRGs induced by peripheral inflammation. Conclusions Our findings reveal a novel mechanism by which preemptive treatment of endomorphins attenuates inflammatory pain through regulating the production of inflammatory cytokines in DRG neurons via inhibition of p38 MAPK phosphorylation. Electronic supplementary material The online version of this article (10.1186/s12974-018-1358-3) contains supplementary material, which is available to authorized users.

Background Atrial fibrillation (AF) is an important arrhythmia associated with cardiovascular morbidity and mortality. This study is focused on exploring the potential relationship between short-term air pollution exposure and occurrence of AF. Methods A case-crossover design was used to investigate the effect of pollutants on AF occurrence among 100 patients from 2013 to 2014. The air pollutants included ambient particulate matter less than 2.5 μm in aerodynamic diameter (PM2.5 ), particulate matter less than 10 μm in aerodynamic diameter (PM10 ), nitrogen dioxide (NO2 ), sulfur dioxide (SO2 ), carbon monoxide (CO), and ozone (O3 ). Participants with cardiac implantable electronic devices implanted were followed-up to December 31, 2014. Results A 10 μg/m3 increase of PM2.5 and PM10 was associated with 3.8% (95% confidence interval [CI]: 1.4-6.2) and 2.7% (95% CI: 0.6-4.8) increase in the risk of AF occurrence, respectively. No statistically significant association was noted with SO2 , NO2 , CO, and O3 . Conclusions Short-term exposure to particular matter, both PM2.5 and PM10 , is associated with an increased risk of AF. This further demonstrates the urgency for air quality monitoring and control in geographical area with intense pollution.

We recently characterized a novel bifunctional agonist for opioid and neuropeptide FF receptors, named BN-9, which exhibited potent analgesia in the mouse tail-flick test when given centrally. To further evaluate its potential therapeutic efficacy for translational-medical development, the current work was performed to explore the antinociceptive activities of intraperitoneal (i.p.) administration of BN-9 in mouse models of tail-flick assay, formalin pain, visceral pain and post-operative pain. In the tail-flick test, BN-9 induced a dose-related antinociceptive effect, which was fully blocked by systemic pretreatment with the peripheral acting opioid receptor antagonist naloxone methiodide, but not supraspinal naloxone methiodide, implying the involvement of the peripheral opioid receptors. In addition, the systemic antinociception of BN-9 was antagonized by the selective antagonists of the μ- and κ-opioid receptors, independently of the δ-opioid and neuropeptide FF receptors. Similarly, dose-dependent analgesia was also produced by systemic BN-9 in different pain models via the peripheral opioid receptors, independently of the neuropeptide FF receptors. Furthermore, the side-effects of systemic BN-9 on motor performance, tolerance development and gastrointestinal transit inhibition were also evaluated. Repeated systemic injection of BN-9 produced non-tolerance analgesia over 8 days. Compared with morphine, intraperitoneal administration of BN-9 exerted less inhibition of gastrointestinal transit. These data show that BN-9 induced systemic analgesia with reduced side-effects on tolerance and constipation. This article suggests that systemic injection of BN-9 causes effective antinociception in different preclinical pain models via the peripheral opioid receptors, providing an attractive approach to develop peripherally acting opioid analgesics with multiple targeting properties.

Cannabinoids (CBs) play important roles in pain modulation. Recently, VD-hemopressin(β) [VD-Hpβ], a 12-residue β-hemoglobin-derived peptide, was reported to activate both CB1 and CB2 receptors in vitro. To further characterize in vivo actions of VD-Hpβ, its antinociceptive activity and site(s) were evaluated in the mouse tail-flick test, and supraspinal antinociception of VD-Hpβ was further assessed in the writhing test. Our results demonstrated that supraspinal, intrathecal, subcutaneous and intraperitoneal administrations of VD-Hpβ produced analgesia in the tail-flick test. When given at the same levels, the CB1 antagonist AM251, rather than the CB2 antagonist AM630 diminished VD-Hpβ-induced antinociception. Furthermore, our results indicated that supraspinal, intrathecal or subcutaneous pretreatment with AM251 significantly inhibited VD-Hpβ-induced systemic antinociception. In the writhing test, supraspinal VD-Hpβ inhibited pain-related behaviors, which was partially prevented by AM251. Notably, supraspinal administration of VD-Hpβ failed to affect motor function at the antinociceptive doses. These findings suggest that VD-Hpβ induces CB1 receptor-mediated antinociception in tail-flick test in various routes of administration, and its systemic antinociception is mediated by both central and peripheral CB1 receptor. In addition, VD-Hpβ produces analgesic activity in the writhing test, which is at least partially mediated by CB1 receptor. Therefore, our present animal models show a CB1 agonistic character of VD-Hpβ, an endogenous cannabinoid peptide.

Objective: The correlation of the BRG1 rs1122608 single nucleotide polymorphism (SNP) with acute myocardial infarction (AMI) has been reported in American and European populations. However, whether rs1122608 acts as a protective factor or a risk factor for AMI is controversial. In this study, we aimed to detect the associations between rs1122608 and the clinical characteristics of AMI as well as susceptibility, gene–environment interactions, and risk factors for AMI in a Chinese Han population. Methods: In this study, 300 AMI patients and 300 healthy controls of Chinese Han ancestry were enrolled. PCR-RFLP was used to genotype rs1122608 SNPs. Genotypic and allelic frequencies of rs1122608 were compared between the AMI and control groups and among four AMI subgroups, which were subdivided by typical symptom, diagnosis time (DT), infarction location andserious complication. Results: Significant differences were detected between the AMI patients and the controls in both the genotypic and allelic frequencies of rs1122608 (p

The authors sought to evaluate the safety and effectiveness of the NeoVas bioresorbable scaffold (BRS) compared with metallic drug-eluting stents.BRS have the potential to improve very late outcomes compared with metallic drug-eluting stents, but some BRS have been associated with increased rates of device thrombosis before complete bioresorption. NeoVas is a new poly-l-lactic acid BRS that elutes sirolimus from a poly-D, l-lactide coating.Eligible patients with a single de novo native coronary artery lesion with a reference vessel diameter 2.5 to 3.75 mm and a lesion length ≤20 mm were randomized 1:1 to NeoVas BRS versus cobalt-chromium everolimus-eluting stents (CoCr-EES). Angiographic follow-up was performed in all patients at 1 year. The primary endpoint was angiographic in-segment late loss (LL), and the major secondary endpoint was the rate of angina. Baseline and follow-up optical coherence tomography and fractional flow reserve were performed in a pre-specified subgroup of patients.The authors randomized 560 patients at 32 centers to treatment with NeoVas (n = 278) versus CoCr-EES (n = 282). One-year in-segment LL with NeoVas and CoCr-EES were 0.14 ± 0.36 mm versus 0.11 ± 0.34 mm (difference 0.03 mm; upper 1-sided 97.5% confidence interval 0.09 mm; pThe NeoVas BRS was noninferior to CoCr-EES for the primary endpoint of 1-year angiographic in-segment LL, and resulted in comparable 1-year clinical outcomes, including recurrent angina. (NeoVas Bioresorbable Coronary Scaffold Randomized Controlled Trial; NCT02305485).

Background: The study aimed to analyze the hospital charges of the inpatients with acute ischemic stroke in Beijing and determine the factors associated with hospital costs. Methods: Medical records of hospitalized patients with a primary diagnosis of ischemic stroke according to International Classification of Diseases 10th Revision codes were collected from 121 hospitals in Beijing from March 1, 2012, to February 28, 2015. Distribution characteristics of hospital charges for different hospital levels (level 2 hospitals and level 3 hospitals) and types (Western medicine hospitals and Chinese medicine hospitals) were studied. Linear regression analysis was used to examine the association among hospital costs and factors that influenced total hospital charges. Results: There were 158,781 admissions for ischemic stroke, 63.1% of the patients were male and their mean age was 67.7 ± 12.4 years, the median length of hospital stay (LOHS) was 13.5 days (interquartile range 9.9–18.1 days). The median hospital charge was 2,112 (1,436–3,147) US dollars. Of these, 46.7% were for medicine, 21.1% for laboratory and examination, and 16.3% for therapy. LOHS, hospital level, and pulmonary infection were key determinants of the hospital charges. Conclusions: The proportion of medicine fees for the ischemic stroke inpatients showed a downward trend during the period from 2012 to 2015, but medicine fees still accounted for the largest percentage of hospital charges in China. LOHS emerged to be the main determinant of the cost. Decreasing medicine fees and LOHS might be strategies to decrease hospital charges and reduce economic burden of stroke in China.

Burn injury is one of the main causes of mortality worldwide and frequently associated with severe and long-lasting pain that compromises the quality of patient life. Several studies have shown that the mu-opioid system plays an important role in burn pain relief. In this study, we investigated the spinal antinociception induced by the endogenous mu-opioid receptor (MOR) agonists endomorphins and explored their mechanisms of actions in burn injury-induced pain model. Our results showed that intrathecal injection of endomorphin-1 and -2 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia via the mu-opioid receptor in mice on day 3 after burn injury, which was consistent with the data obtained from the mu-opioid receptor knockout mice. Western blot showed that the phosphorylation levels of extracellular signal-regulated kinase1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in ipsilateral spinal cord tissues were significantly up-regulated after burn injury. Intrathecal injection of endomorphins selectively inhibited the activation of p38 MAPK on day 3 after burn injury via the mu-opioid receptor. Further studies found that repeated application of the specific p38 MAPK inhibitor SB203580 dose-dependently inhibited burn-injury pain, as well as the activation of spinal p38 MAPK. Taken together, our present study demonstrates that intrathecal injection of endomorphins attenuates burn-injury pain in male mice by affecting the spinal activation of p38 MAPK via the mu-opioid receptor.

The activation of opioid and neuropeptide FF (NPFF) receptors plays important roles to modulate nociceptive signal in inflammatory pain states. Recently, BN-9 (Tyr-D. Ala-Gly-Phe-Gln-Pro-Gln-Arg-Phe-NH2) was pharmacologically characterized as a novel bifunctional agonist at both opioid and NPFF receptors. In the present study, the anti-allodynic activity and site(s) of action of BN-9 were assessed in a mouse model of carrageenan-induced inflammatory pain. In mice, BN-9 induced a dose-dependent anti-allodinic effect through opioid receptor at supraspinal or spinal level, and this effect was augmented by pretreatment with the NPFF receptor antagonist at the same level. In contrast, peripheral administration of BN-9 produced opioid receptor-mediated anti-allodynia, which was insensitive of the NPFF receptor antagonist. In addition, systemic BN-9 produced anti-allodynic effect via opioid receptors, independent of NPFF system. Therefore, these data indicate that central, peripheral or systemic administrations of BN-9 exert potent analgesic activities in inflammatory pain model via opioid receptor, and central effects of BN-9 are associated with NPFF system. Interestingly, systemic anti-allodynia of BN-9 was blocked by intraperitoneal administration of the opioid receptor antagonists, naloxone and naloxone methiodide, but not by intracerebroventricular injection of the peripherally acting opioid antagonist naloxone methiodide. Furthermore, BN-9-induced systemic anti-allodynia was reversed by intraplantar administration of naloxone, but not by peripheral administration of the NPFF receptor antagonist. Taken together, our data further suggest that systemic BN-9-induced anti-allodynic effect is mainly mediated by peripheral opioid receptors, independent of NPFF receptors.

Isolated left ventricular non-compaction (LVNC) is a rare cardiomyopathy that leads to severe clinical complications. This study is to investigate whether or not prolonged QTc is a good indicator for evaluating the severity of fibrosis and predicting the prognosis of LVNC, and if native T1 can be used to quantify the fibrosis. 32 LVNC patients and 14 healthy controls with matched age and sex were examined by CMR and ECG to acquire native T1, QTc interval, and ECG abnormalities. 18 LVNC patients had normal QTc and 14 LVNC patients had prolonged QTc. The mean native T1 value of the normal controls, normal QTc and prolonged QTc patients was 1096.0 ± 41.5, 1141.98 ± 45.46, and 1182.67 ± 42.02 ms, respectively. One-way ANVOA showed significant differences in native T1 among three groups (F = 14.9, p

Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. Moreover, hemopressin and its truncated peptides were also reported to produce a slight modulatory effect on opioid system. In the present work, based on the amino acid sequence analyses of hemoglobin subunit α, rat VD-hemopressin(α) [(r)VD-Hpα] was predicted as a cannabinoid peptide derived from rat α-hemoglobin. Furthermore, (r)VD-Hpα was synthesized and characterized in a series of in vitro and in vivo assays. Our results demonstrated that (r)VD-Hpα induced neurite outgrowth in Neuro 2A cells via CB1 receptor. In the tail-flick assay, (r)VD-Hpα dose-dependently exerted central antinociception through CB1 receptor, but not CB2 and opioid receptors. In mice, supraspinal administration of (r)VD-Hpα produced dose-dependent hypothermia, which was partially reduced by the CB1 receptor antagonist AM251, but not by the antagonists of CB2 and opioid receptors. In addition, (r)VD-Hpα caused hypoactivity after intracerebroventricular injection, and this effect was insensitive to the antagonists of cannabinoid and opioid receptors. Further assessment of the side-effects demonstrated that (r)VD-Hpα evoked the limited effects on gastrointestinal transit at antinociceptive doses, but repeated i.c.v. injection of (r)VD-Hpα induced development of antinociceptive tolerance. Taken together, these data suggest that the predicted peptide (r)VD-Hpα produces antinociception, hypothermia and hypoactivity via different pharmacological mechanisms, at least partially, which may offer an attractive strategy for separating cannabinoid analgesia from hypoactivity. Moreover, it implies that (r)VD-Hpα has therapeutic potential in pain management with limited side-effects.

Background: Q fever endocarditis, a chronic illness caused by Coxiella burnetii, can be fatal if misdiagnosed or left untreated. Despite a relatively high positive rate of Q fever serology in healthy individuals in the mainland of China, very few cases of Q fever endocarditis have been reported. This study summarized cases of Q fever endocarditis among blood culture negative endocarditis (BCNE) patients and discussed factors attributing to the low diagnostic rate. Methods: We identified confirmed cases of Q fever endocarditis among 637 consecutive patients with infective endocarditis (IE) in the Peking Union Medical College Hospital between 2006 and 2016. The clinical findings for each confirmed case were recorded. BCNE patients were also examined and each BCNE patient’s Q fever risk factors were identified. The risk factors and presence of Q fever serologic testing between BCNE patients suspected and unsuspected of Q fever were compared using the Chi-squared or Chi-squared with Yates’ correction for continuity. Results: Among the IE patients examined, there were 147 BCNE patients, of whom only 11 patients (7.5%) were suspected of Q fever and undergone serological testing for C. burnetii. Six out of 11 suspected cases were diagnosed as Q fever endocarditis. For the remaining 136 BCNE patients, none of them was suspected of Q fever nor underwent relevant testing. Risk factors for Q fever endocarditis were comparable between suspected and unsuspected patients, with the most common risk factors being valvulopathy in both groups. However, significantly more patients had consulted the Infectious Diseases Division and undergone comprehensive diagnostic tests in the suspected group than the unsuspected group (100% vs. 63%, P = 0.03). Conclusions: Q fever endocarditis is a serious yet treatable condition. Lacking awareness of the disease may prevent BCNE patients from being identified, despite having Q fever risk factors. Increasing awareness and guideline adherence are crucial in avoiding misdiagnosing and missed diagnosing of the disease. Key words: Blood Culture; Endocarditis; Q Fever

Dementia frequently occurs in Down syndrome (DS) patients, and early intervention is important in its management. We have previously demonstrated a positive correlation of plasma β-amyloid Aβ42 levels and negative correlations of Aβ40 and tau levels with dementia in DS. In this study, we examined more cases and constructed composite scores with both tau and amyloids to correlate with dementia in DS. Plasma Aβ42, Aβ40, and tau proteins were measured by an immunomagnetic reduction assay in DS patients. Data were randomly and repeatedly split into training and validating sets, and logistic regression was applied to calculate the area under the curve (AUC) for each biomarker. A total of 73 DS patients (among them, 23 had neurodegeneration) and 77 controls were recruited. In DS patients without dementia, plasma Aβ40 and tau levels were highly elevated, but Aβ42 levels were lower than those of the healthy controls. DS patients with dementia, compared with DS patients with no dementia, had a large decline in Aβ40 and tau but a rise in Aβ42. For biomarker scores correlating with dementia, Aβ40 revealed an AUC of 0.912; the composite score of Aβ40 × tau revealed an AUC of 0.953; and a combined composite score of 0.1 for Aβ40 × Tau +0.9 Tau × Aβ40/Aβ42 achieved the highest AUC of 0.965. Therefore, composite biomarker scores including both plasma tau and β-amyloid levels correlate with dementia in DS better than using individual biomarker scores. The pattern of tau decline and Aβ42 rise in DS patients with dementia are also different from previous findings in Alzheimer's disease.

Background: The association between interleukin-8 (IL-8) gene polymorphism −251 A>T and susceptibility to coronary artery disease (CAD) has been investigated previously; however, results remain controversial. Thus, a meta-analysis was conducted to reassess the effects of this polymorphism on CAD risks. Methods: The PubMed, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched for relevant studies published up to December, 2018. The pooled odds ratios (OR) were calculated using STATA 13.0 software for allelic (A vs T) as well as homozygote (AA vs TT), heterozygote (AT vs TT), recessive (AA vs AT + TT), and dominant (AA + AT vs TT) genotype models, respectively. Results: Ten case-control studies (3744 cases and 3660 controls) were included. Overall, a significant association of IL-8 gene −251 A > T polymorphism with an increased risk of CAD was only observed in the dominant genotype model (OR = 1.48), but not others. In the subgroup analysis, significantly increased risks were also found for Chinese (OR = 1.64), polymerase chain reaction-restriction fragment length polymorphism genotyping (OR = 1.61), acute coronary syndrome (ACS) type (OR = 1.92 for 3 datasets; OR = 1.88 for 4 datasets), high quality (OR = 1.64), and age/gender matching status (OR = 1.55) under the dominant model. Furthermore, significantly increased risks were also found for ACS type under allelic (OR = 1.32 for 3 datasets; OR = 127 for 4 datasets), homozygote (OR = 1.64 for 3 datasets; OR = 1.50 for 4 datasets), heterozygote (OR = 1.32 for 3 datasets; OR = 1.30 for 4 datasets), and recessive (OR = 1.40 for 3 datasets; OR = 1.28 for 4 datasets) models. Conclusion: This meta-analysis suggests that Chinese patients carrying −251A allele of IL-8 may have an increased risk for the development of CAD, especially ACS.

Background The nonapeptide DN-9 functions as a multifunctional agonist to opioid and neuropeptide FF (NPFF) receptors and exhibits antinociceptive effects at the central and peripheral levels. Methods The effects of DN-9 on small and colonic intestinal transit were evaluated using the upper gastrointestinal (GI) transit test and colonic bead expulsion assay, respectively. Opioid and NPFF receptor antagonists were used to investigate the mechanisms of DN-9-induced GI inhibition. Furthermore, the agonism of the DN-9 analog [Phg9 ]-DN-9 to opioid and NPFF receptors was tested by the cAMP assay. Key results Intracerebroventricular administration of DN-9 dose-dependently slowed upper GI transit and colonic expulsion via mu- and kappa-opioid receptors in the brain, independent of the delta-opioid receptor. Similarly, intraperitoneal injection of DN-9 dose-dependently inhibited GI propulsion via the peripheral opioid receptors. DN-9-induced GI transit inhibitions were significantly aggravated by the NPFF receptor antagonist RF9. Moreover, the DN-9 analog [Phg9 ]-DN-9, an agonist at mu-, delta-, and kappa-opioid receptors but not NPFF receptors, inhibited GI more potently than DN-9. In addition, intracerebroventricular NPFF significantly attenuated the central inhibitory effects induced by [Phg9 ]-DN-9 and morphine. However, central and peripheral injections of NPFF or RF9 almost had no significant effects on GI transit by itself. Conclusion and inferences Intracerebroventricular and intraperitoneal administrations of DN-9 inhibit GI transit via opioid receptors in mice by central and peripheral mechanisms, respectively. In addition, the NPFF agonism of DN-9 possesses antiopioid effects on GI transit, which might explain the reduced constipation at the antinociceptive doses.

Background Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized progressive cardiomyopathy with heterogenous clinical manifestations that lead to its misdiagnosis and poor prognosis. This study was performed to describe the clinical characteristics and natural history of Chinese patients to improve clinical awareness of this condition. Methods In this study, we retrospectively investigated 23 patients with a confirmed diagnosis of hereditary ATTR-CM in Peking Union Medical College hospital from From January 1, 2000 to December 31, 2018. Results In all, 16 patients (69.6%) were males, the median age at disease onset was 45 (33,55) years old. The median duration from symptom onset to diagnosis was 30 (18,46) months. Phenotypes were classified as exclusively cardiac (n = 1, 4.3%) and mixed type (n = 22, 95.6%). The common mutations were Gly47Arg (7 patients [30.4%]) and Val30Ala (3 patients [13%]). Ventricular hypertrophy was observed in 23 (100%) patients, the mean thickness of the ventricular septum was 16.1 ± 3.9 mm, the mean thickness of the left ventricular posterior wall was 15.1 ± 2.8 mm. The mean left ventricle ejection fraction (LVEF) was 57.3 ± 11.9% and only 5 patients (21.7%) had LVEF P = 0.045]. Conclusions The clinical characteristics of ATTR are heterogeneous: men are more likely to be affected and onset symptoms are not obvious in the heart and mainly include peripheral neuropathy and autonomic neuropathy; however, LV hypertrophy, especially a thick ventricular septum and posterior wall with preserved LVEF, are often detected on echocardiography. Abnormal ECG manifestations are common. The prognosis is poor, and patients with EF > 50% have better survival. Clinicians should be more aware of the complex clinical profile of ATTR amyloidosis to avoid misdiagnosis in practice.

The efficacy of hemiarch replacement combined with a modified triple-branched stent graft in Debakey type I aortic dissection remains to be confirmed.From January 2016 to December 2017, 167 patients with acute Debakey type I aortic dissection underwent hemiarch replacement combined with a modified triple-branched stent graft. The clinical and imaging data were retrospectively analyzed. The early composite endpoint was defined to comprise perioperative mortality, permanent neurologic deficits, and renal failure requiring hemodialysis at discharge.The overall 30-day mortality was 4.2% (7 of 167). The incidence of the composite endpoint was 11.4% (19 of 167). The risk factors for the composite endpoint were malperfusion syndrome (odds ratio 5.17; 95% confidence interval, 1.46 to 18.35; P = .011) and creatine greater than 1.5 mg/dL (odds ratio 5.44; 95% confidence interval, 2.27 to 13.06; P.001). The overall survival was 94% at 1 year and 92.2% at 2 years during a median follow-up of 20.9 ± 9.6 months. Three patients required distal aorta reintervention. Complete thrombosis in the false lumen of the descending aorta at the level of the pulmonary bifurcation and at the level of the celiac trunk was observed in 98.8% and 10.8% of the patients, respectively.Hemiarch replacement combined with a modified triple-branched stent graft is a reliable technique for acute Debakey type I aortic dissection as indicated by 2 years of follow-up.

AIMS Our aim is to investigate the characterized echocardiographic cardiac measurements of POEMS syndrome and determine its relationship with clinical manifestations. METHODS AND RESULTS The cross-sectional study included 27 treatment-naive patients with newly diagnosed POEMS syndrome and 26 age- and sex-matched healthy volunteers. Information of clinical manifestations, serological tests, pulmonary function tests, and both conventional echocardiograph and tissue Doppler imaging (TDI) were collected and analyzed. Pearson's correlation coefficient was used for determining the related clinical and echocardiographic parameters. Compared to healthy people, left ventricular (LV) mass index (LVMI) was elevated in patients with POEMS syndrome (41.3 ± 11.0 g/m2.7 , P

The development of multitarget opioid drugs has emerged as an attractive therapeutic strategy to eliminate opioid-related side effects. Our previous study developed a series of opioid and neuropeptide FF pharmacophore-containing chimeric peptides, including DN-9 (Tyr-D.Ala-Gly-NMe.Phe-Gly-Pro-Gln-Arg-Phe-NH2), which produced potent nontolerance forming analgesia at the supraspinal level. In the present study, the antinociceptive effects of DN-9 in a series of preclinical pain models and the potential side-effects were investigated at the spinal level in mice. In the tail-flick test, intrathecal injection of DN-9 produced potent analgesia with an ED50 value at 1.33 pmol, and the spinal antinociception of DN-9 was mainly mediated by μ- and κ-opioid receptors. In addition, DN-9-induced spinal antinociception was augmented by the neuropeptide FF receptors antagonist. Furthermore, DN-9 could decrease both the frequency and amplitude of sEPSCs in lamina IIo neurons of the spinal cord, which were mediated by opioid receptors. In contrast to morphine, chronic intrathecal treatments with DN-9 did not induce analgesic tolerance, c-Fos expression or microglial activation. Intrathecal injection of DN-9 showed potent analgesia with antinociceptive ED50 values between .66 and 55.04 pmol in different pain models, including the formalin test, acetic acid-induced writhing test, carrageenan-induced inflammatory pain and neuropathic pain. Moreover, DN-9 did not show side effects in locomotor function and coordination, gastrointestinal transit inhibition, the cardiovascular system, and body temperature regulation at antinociceptive doses. Taken together, the present study showed DN-9 produced effective, nontolerance forming analgesia with reduced side effects at the spinal level. DN-9 might be a promising compound for developing multifunctional opioid analgesics with limited adverse effects. PERSPECTIVE: This article presents the potent and nontolerance forming analgesia effects of DN-9 in a series of preclinical pain models with less opioid related adverse effects at the spinal level in mice. This study also demonstrates that DN-9 has translational potential into an intrathecal analgesic.

Background The clinical features, angiographic findings, and outcomes have not been compared between pediatric and adult patients with Takayasu arteritis (TA) with coronary involvement. Methods Of 1056 consecutive patients with TA hospitalized and followed from 1990 to 2018 in our hospital, 38 patients including 9 children and 29 adults (mean age at diagnosis of 14.3 ± 3.3 years and 38.6 ± 12.0 years, respectively) were diagnosed with coronary artery involvement by imaging. Clinical manifestations, coronary lesion characteristics, and outcomes were compared between the pediatric and adult patients. Results Compared with adults, pediatric patients with TA with coronary involvement had a significantly shorter disease duration (median, 2 months; interquartile range [IQR], 1-38 vs median, 48 months [IQR, 18-90], P = 0.019) and higher disease activity score (median, 3 [IQR, 2-4] vs median, 2 [IQR, 1-3], P = 0.013) on the first positive coronary assessment. Although all recruited patients except 1 child had coronary stenosis, coronary aneurysmal dilation was found in 6 patients and was more frequent in children than in adults (55.6% vs 3.4%, P = 0.001). Moreover, the children with coronary aneurysmal dilation had a higher incidence of dilation in large vessels than children without aneurysmal dilation (80.0% vs 0%, P = 0.048). Conclusion Pediatric patients with TA with coronary involvement had higher inflammation status and were more prone to coronary aneurysmal dilation on the first positive coronary assessment compared with adults. Dilation in the aorta and its major branches might be an indicator of coronary aneurysmal dilation in these pediatric patients.

BACKGROUND AND PURPOSE: Considerable effort has recently been directed at developing multifunctional opioid drugs to minimize the unwanted side effects of opioid analgesics. We have developed a novel multifunctional opioid agonist, DN‐9. Here, we studied the analgesic profiles and related side effects of peripheral DN‐9 in various pain models. EXPERIMENTAL APPROACH: Antinociceptive effects of DN‐9 were assessed in nociceptive, inflammatory, and neuropathic pain. Whole‐cell patch‐clamp and calcium imaging assays were used to evaluate the inhibitory effects of DN‐9 to calcium current and high‐K(+)‐induced intracellular calcium ([Ca(2+)](i)) on dorsal root ganglion (DRG) neurons respectively. Side effects of DN‐9 were evaluated in antinociceptive tolerance, abuse, gastrointestinal transit, and rotarod tests. KEY RESULTS: DN‐9, given subcutaneously, dose‐dependently produced antinociception via peripheral opioid receptors in different pain models without sex difference. In addition, DN‐9 exhibited more potent ability than morphine to inhibit calcium current and high‐K(+)‐induced [Ca(2+)](i) in DRG neurons. Repeated treatment with DN‐9 produced equivalent antinociception for 8 days in multiple pain models, and DN‐9 also maintained potent analgesia in morphine‐tolerant mice. Furthermore, chronic DN‐9 administration had no apparent effect on the microglial activation of spinal cord. After subcutaneous injection, DN‐9 exhibited less abuse potential than morphine, as was gastroparesis and effects on motor coordination. CONCLUSIONS AND IMPLICATIONS: DN‐9 produces potent analgesia with minimal side effects, which strengthen the candidacy of peripherally acting opioids with multifunctional agonistic properties to enter human studies to alleviate the current highly problematic misuse of classic opioids on a large scale.

The opioid and neuropeptide FF pharmacophore-containing chimeric peptide 0 (BN-9) was recently developed and produced potent nontolerance forming analgesia. In this study, 11 analogues of 0 were designed and synthesized. An in vitro cAMP assay demonstrated that these analogues behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogues produced potent nontolerance forming antinociception. Notably, 11 (DN-9) was 33-fold more potent than 0 at analgesic effects, which was mediated by μ- and κ-opioid receptors. In addition, 11 also produced powerful analgesic effects in the formalin pain and CFA-induced chronic inflammatory pain models. Strikingly, following its repeated administration for 6 days, 11 did not produce antinociceptive tolerance in the tail-flick test and CFA-induced pain model. The present work indicates that it is reasonable to design multifunctional peptide ligands for opioid and NPFF receptors in a single molecule producing effective nontolerance forming antinociception.

Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of κ-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by κ-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of κ-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects.

Immunoglobulin E (IgE), a key element of allergic reactions, was considered to be involved in the development of atherosclerosis and the pathogenesis of myocardial ischemia. This study was designed to test whether total serum IgE levels were associated with the atherosclerosis severity of coronary artery disease (CAD).Total serum IgE concentrations were measured in 708 consecutive patients who were presented to our center for coronary angiography. Atherosclerosis severity of CAD was assessed by the number of diseased vessels showing ≥50% diameter stenosis and quantified by Gensini score.Patients with CAD (N = 562) had higher serum IgE levels than those without CAD (N = 146) [55.90 (19.10-156.00) vs. 26.90 (11.80-62.10) KU/L, p = 0.003]. Furthermore, the serum IgE levels were significantly increased in patients with multivessel disease (MVD) compared to those with single-vessel disease [61.80 (23.20-159.00) vs. 32.45(14.15-94.38) KU/L, p = 0.003]. After adjustment for traditional cardiovascular risk factors, a high serum IgE level was an independent predictor for an increased risk of MVD (OR 1.003; 95% CI 1.001-1.004; p = 0.041). Receiver-operating characteristic curve analysis demonstrated that serum IgE levels improved the predictive capability of traditional risk factors for MVD (area under the curve with and without IgE: 0.734 and 0.713, respectively, p 0.001). Meanwhile, there was a significant linear relationship between Gensini score and the serum IgE level quartiles (p for linear trend0.001).Increased total serum IgE levels are associated with MVD and contribute to discriminating CAD severity independently of traditional cardiovascular risk factors.

Background Light-chain amyloidosis (AL) is a plasma cell disorder characterized by the extracellular deposition of insoluble fibril-forming monoclonal immunoglobulin, aggregating in heart and leading to cardiac amyloidosis (CA). Transthoracic echocardiography is a noninvasive method used for the evaluation of cardiac diastolic dysfunction. The left atrium (LA) plays an important role in modulating cardiovascular performance, with its function participating left ventricular filling and its size being affected by diastolic function. Therefore, we aimed to assess prognostic values of LA size measured by a simple echocardiographic parameter, LA diameter indexed to body surface area, in CA and to explore risk factors associated with LA enlargement as well as the incidence of severe heart failure (HF). Materials and Methods A retrospective analysis of echocardiography of patients with biopsy-proven cardiac AL amyloidosis was conducted. LA enlargement was defined as LA diameter indexed to body surface area greater than 23 mm/m 2 . Results A total of 104 patients with CA were included in the final analysis, 61 (58.7%) of which showed a presentation of LA enlargement. Age, New York Heart Association, ejection fraction and early-to-atrial transmitral flow velocity ratio were independently associated with LA enlargement. During a mean follow-up period of 39 months, LA enlargement was strongly related with all-cause mortality (hazard ratio = 1.94; 95% CI: 1.14-3.29; P = 0.015) and increased risk of severe HF (hazard ratio = 2.18; 95% CI: 1.12-4.23; P = 0.022). Conclusions In cardiac AL amyloidosis, age and early-to-atrial transmitral flow velocity ratio were main independent risk factors with regard to LA enlargement. LA enlargement was strongly associated with incidence of severe HF and was also a significant predictor of all-cause mortality.

Chronic opioids treatment is impeded by the development of analgesic tolerance and opioid-induced hyperalgesia. Recent studies have shown that multi-functional opioid compounds produce analgesic activities with limited side effects. We developed a novel multi-functional peptide targeting opioid and neuropeptide FF receptors named BN-9, which produced potent and non-tolerance forming antinociceptive effect after supraspinal and systemic administrations. In the present study, the analgesic properties and potential side effects of intrathecal BN-9 were investigated in a range of preclinical rodent models. In complete Freund's adjuvant-induced inflammatory pain model, intrathecal BN-9 dose-dependently produced analgesic effect via opioid receptors, and the spinal antinociceptive effect was augmented by the neuropeptide FF receptor antagonist RF9. In contrast, in plantar incision-induced postoperative pain model, BN-9 exhibited potent anti-allodynic effect via opioid receptors and, at least partially, neuropeptide FF receptors. In mouse models of acetic acid-induced visceral pain and formalin pain, BN-9-induced spinal antinociception was mainly mediated by opioid receptors, independent of neuropeptide FF receptors. Furthermore, at the spinal level, chronic treatments with BN-9 did not lead to analgesic tolerance and cross-tolerance to morphine. Moreover, opioid-induced hyperalgesia was observed after repeated administration of morphine, but not BN-9. Taken together, our present study suggests that intrathecal BN-9 produces potent and non-tolerance forming antinociception, and does not cause opioid-induced hyperalgesia. Thus, BN-9 might serve as a promising lead compound in the development of multi-functional opioid analgesics with minimized side effects.

Right ventricular (RV) function has been identified as an important determinant of outcome in patients with pulmonary hypertension. We aimed to investigate the relationship between echocardiographic-derived RV function and health-related quality of life (HRQOL) in patients with systemic lupus erythematosus associated pulmonary arterial hypertension (SLE-APAH), and to identify the best echocardiographic parameter for evaluating RV function in these patients.Sixty (60) consecutive patients with SLE-APAH (all female, mean age 33.6±8.2years) were recruited from May 2013 to November 2014. Echocardiograph, right heart catheterisation, SLE disease activity index (SLEDAI), and functional status and SF-36 generic questionnaire were assessed.Echocardiograph-derived RV systolic function was significantly correlated with haemodynamics (p0.05), with tricuspid annular plane systolic excursion (TAPSE) showing the strongest correlation with pulmonary vascular resistance (RTAPSE is a useful index for RV function assessment, and is associated with HRQOL in patients with SLE-APAH.

BACKGROUND AND PURPOSE: The voltage‐gated sodium channel Na(V)1.7 is considered a therapeutic target for pain treatment based on human genetic evidence. GpTx‐1 and its potent analogue [Ala(5), Phe(6), Leu(26), Arg(28)]GpTx‐1 (GpTx‐1‐71) were recently characterized as Na(V)1.7 inhibitors in vitro. Furthermore, the present work was conducted to investigate the analgesic properties of these two peptides in different pain models after spinal administration. EXPERIMENTAL APPROACH: The antinociceptive activities of both GpTx‐1 and GpTx‐1‐71 were investigated in mouse models of acute, visceral, inflammatory and neuropathic pain. Furthermore, the side effects of GpTx‐1 and GpTx‐1‐71 were evaluated in rotarod, antinociceptive tolerance, acute hyperlocomotion and gastrointestinal transit tests. KEY RESULTS: The i.t. administration of both GpTx‐1 and GpTx‐1‐71 dose‐dependently produced powerful antinociception in the different pain models. This effect was attenuated by the opioid receptor antagonist naloxone, suggesting the involvement of the opioid system. In this study, repeated administration of these two_peptides produced spinal analgesia without a loss of potency over 8 days in mouse models of acute, inflammatory and neuropathic pain. Moreover, spinal administration of GpTx‐1 and GpTx‐1‐71 did not induce significant effects on motor coordination, evoke acute hyperlocomotion or increase gastrointestinal transit time. CONCLUSIONS AND IMPLICATIONS: Our data indicate that the Na(V)1.7 peptide inhibitors GpTx‐1 and GpTx‐1‐71 produce powerful, nontolerance‐forming analgesia in preclinical pain models, which might be dependent on the endogenous opioid system. In addition, at the spinal level, the limited side effects imply that these Na(V)1.7 peptide inhibitors could be potentially developed as GpTx‐1‐based drugs for pain relief.

Neuropeptide FF (NPFF) system has recently been reported to modulate cannabinoid-induced antinociception. The aim of the present study was to further investigate the roles of NPFF system in the antinociceptive effects induced by intracerebroventricular (i.c.v.) administration of mouse VD-hemopressin(α), a novel endogenous agonist of cannabinoid CB1 receptor, in naive and VD-hemopressin(α)-tolerant mice. The effects of NPFF system on the antinociception induced by VD-hemopressin(α) were investigated in the radiant heat tail-flick test in naive mice and VD-hemopressin(α)-tolerant mice. The cannabinoid-tolerant mice were produced by given daily injections of VD-hemopressin(α) (20 nmol, i.c.v.) for 5 days and the antinociception was measured on day 6. In naive mice, intracerebroventricular injection of NPFF dose-dependently attenuated central analgesia of VD-hemopressin(α). In contrast, neuropeptide VF (NPVF) and D.NP(N-Me)AFLFQPQRF-NH2 (dNPA), two highly selective agonists for Neuropeptide FF1 and Neuropeptide FF2 receptors, enhanced VD-hemopressin(α)-induced antinociception in a dose-dependent manner. In addition, the VD-hemopressin(α)-modulating activities of NPFF and related peptides were antagonized by the Neuropeptide FF receptors selective antagonist 1-adamantanecarbonyl-RF-NH2 (RF9). In VD-hemopressin(α)-tolerant mice, NPFF failed to modify VD-hemopressin(α)-induced antinociception. However, both neuropeptide VF and dNPA dose-dependently potentiated the antinociception of VD-hemopressin(α) and these cannabinoid-potentiating effects were reduced by RF9. The present works support the cannabinoid-modulating character of NPFF system in naive and cannabinoid-tolerant mice. In addition, the data suggest that a chronic cannabinoid treatment modifies the pharmacological profiles of NPFF, but not the cannabinoid-potentiating effects of neuropeptide VF and dNPA.